Univariate Hazard Ratio Research Articles

Prognostic Significance of Hyperuricemia in Patients With Acute Heart Failure

Serum uric acid (UA) is associated with death and hospitalization in chronic heart failure (HF). However, UA in acute HF has not been well studied with respect to its relation to renal dysfunction and vascular congestion. We measured admission serum UA along with baseline variables in 281 patients with acute HF screened from the Loop Diuretics Administration and Acute Heart Failure (Diur-HF) trial. Hyperuricemia was defined as serum UA >7mg/dl in men and >6mg/dl in women. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate <60ml/min/1.73m(2) before hospital admission. Death or HF hospitalization at 6months was the primary outcome. The mean UA concentration was 6.4 ± 2.5mg/dl, and 121 patients (43.1%) were classified as hyperuricemic. UA values were significantly increased in patients with CKD compared to patients without CKD (6.8 ± 2.7 vs 6.1 ± 2.1mg/dl; p= 0.02); however, UA was not associated with the development of acute kidney injury. Patients with hyperuricemia had greater degrees of pulmonary and systemic congestion than normouricemic patients (congestion score 3.5 vs 2.1, p <0.01). Hyperuricemia was associated with higher risk of death or HF rehospitalization (univariate hazard ratio 1.46 [1.02 to 2.10]; p= 0.04, multivariate hazard ratio 1.69 [1.16 to 2.45]; p= 0.005). In conclusion, hospitalized patients with acute HF, elevated UA levels were associated with both CKD and pulmonary congestion. After controlling for potential confounders, hyperuricemia was associated with rehospitalization and death at 6months.

Intradialytic Hypoxemia and Clinical Outcomes in Patients on Hemodialysis.

Intradialytic hypoxemia has been recognized for decades, but its associations with outcomes have not yet been assessed in a large patient cohort. Our retrospective cohort study was conducted between January of 2012 and January of 2015. We recorded blood oxygen saturation every minute during hemodialysis in patients with arteriovenous access. A 6-month baseline period with at least 10 treatments with oxygen saturation measurements preceded a 12-month follow-up. Patients were stratified by the presence or absence of prolonged intradialytic hypoxemia defined as oxygen saturation <90% for at least one third of the treatment time. Demographic, laboratory, and treatment data and hospitalization and mortality rates were compared between the groups. Multivariate Cox regression analysis was used to assess baseline predictors of all-cause mortality during follow-up. In total, 100 (10%) of 983 patients had prolonged intradialytic hypoxemia. These patients were older (+3.6 years; 95% confidence interval, 0.8 to 6.3), had longer dialysis vintage (+1.2 years; 95% confidence interval, 0.3 to 2.1), and had higher prevalence of congestive heart failure (+10.8%; 95% confidence interval, 1.6 to 20.7) and chronic obstructive pulmonary disease (+13%; 95% confidence interval, 5 to 21.2). They also resembled an inflammatory phenotype, with lower serum albumin levels (-0.1 g/dl; 95% confidence interval, -0.2 to 0) and higher neutrophil-to-lymphocyte ratios (+1; 95% confidence interval, 0.5 to 1.6). They had lower hemoglobin levels (-0.2 g/dl; 95% confidence interval, -0.4 to 0) and required more erythropoietin (+1374 U per hemodialysis treatment; 95% confidence interval, 343 to 2405). During follow-up, all-cause hospitalization (1113 hospitalizations; univariate hazard ratio, 1.46; 95% confidence interval, 1.22 to 1.73) and mortality (89 deaths; adjusted hazard ratio, 1.98; 95% confidence interval, 1.14 to 3.43) were higher in patients with prolonged intradialytic hypoxemia. Prolonged intradialytic hypoxemia was associated with laboratory indicators of inflammation, higher erythropoietin requirements, and higher all-cause hospitalization and mortality.

Diabetes, glucose tolerance, and the risk of sudden cardiac death.

BackgroundDiabetes predisposes to sudden cardiac death (SCD). However, it is uncertain whether greater proportion of cardiac deaths are sudden among diabetes patients than other subjects. It is also unclear whether the risk of SCD is pronounced already early in the course of the disease. The relationship of impaired glucose tolerance (IGT) and SCD is scarcely documented.MethodsA general population cohort of 10594 middle-aged subjects (mean age 44 years, 52.6 % male, follow-up duration 35–41 years) was divided into diabetes patients (n = 82), subjects with IGT (n = 3806, plasma glucose ≥9.58 mmol/l in one-hour glucose tolerance test), and controls (n = 6706).ResultsDiabetes patients had an increased risk of SCD after adjustment confounders (hazard ratio 2.62, 95 % confidence interval 1.46–4.70, p = 0.001) but risk for non-sudden cardiac death was similarly increased and the proportion of SCD of cardiac deaths was not increased. The SCD risk persisted after exclusion of subjects with baseline cardiac disease or non-fatal cardiac events during the follow-up. Subjects with IGT were at increased risk for SCD (univariate hazard ratio 1.51; 95 % confidence interval 1.31–1.74; p < 0.001) and also for non-sudden cardiac deaths and non-fatal cardiac events but adjustments for other risk factors attenuated these effects.ConclusionsDiabetes was associated with increased risk of SCD but also the risk of non-sudden cardiac death was similarly increased. The proportion of cardiac deaths being sudden in subjects with diabetes was not increased. The higher SCD risk in diabetes patients was independent of known cardiac disease at baseline or occurrence of non-fatal cardiac event during the follow-up.

Abstract P3-07-21: Non-alcoholic fatty liver disease induced by selective estrogen receptor modulators is a protective factor for breast cancer survival

Abstract Purpose: Non-alcoholic fatty liver disease (NAFLD) induced by selective estrogen receptor modulators (SERMs) treatment may be related to treatment efficacy for the antagonism of circulating estrogens. We conducted a retrospective study to investigate the relationship between survival outcomes and NAFLD in breast cancer patients treated with tamoxifen or toremifene. Patients and methods: 785 eligible patients received tamoxifen or toremifene in Sun Yat-sen university cancer center from January 2005 to December 2009 were included in our study. All patients have at less one abdominal ultrasonography measurement at baseline and every year's follow-up. Patients who diagnosed NAFLD by ultrasonography during three-year's follow-up were classified into NAFLD cohort, others were classified into no-NAFLD cohort. Univariate and multivariate Cox regression was utilized to analyse the relationship between NAFLD and disease-free survival (DFS) and overall survival (OS). Results:158 patients had reported NAFLD in the first 3 years' follow-up. Patients who developed NAFLD had better DFS and OS than those not developing NAFLD. The 5-years DFS was 91.56% and 85.01% at NAFLD and no-NAFLD cohort (univariate hazard ratio [HR]: 0.59 [95%CI 0.37-0.96], P=0.034), respectively. The 5-years OS was 96.64% and 93.31% at NAFLD and no-NAFLD cohort (univariate HR: 0.39 [95%CI 0.16-0.99], P=0.047), respectively. Multivariate analysis revealed that NAFLD is an independent prognostic factor on DFS in breast cancer patients with SERMs treated. Women treated with SERMs experienced NAFLD in the first three-year's follow-up had a reduced risk of DFS of 42% (multivariate HR: 0.58; [95%CI 0.36-0.95], P=0.032) compared with patients without NAFLD. Conclusion: NAFLD induced by SERMs seems to be associated with better survival outcomes and may therefore be helpful in predicting treatment responses in breast cancer patients treated with SERMs. Citation Format: Wang S, Zheng Q, Nie M, Xu F, Xia W, Yuan Z, Peng R, An X, Qin T, Qin G. Non-alcoholic fatty liver disease induced by selective estrogen receptor modulators is a protective factor for breast cancer survival. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-21.

Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti-U1 RNP-positive patients with CTD-associated PAH, with a focus on systemic sclerosis (SSc)-associated PAH. We implemented a prospective database that included patients with CTD-associated PAH for whom there were clinical, autoantibody, and mortality data. We compared clinical and hemodynamic characteristics to anti-U1 RNP antibody status. We then assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc-associated PAH. We studied a total of 342 patients with CTD-associated PAH, of whom 36 (11%) were anti-U1 RNP antibody positive. Anti-U1 RNP-positive patients were younger and less functionally impaired than were anti-U1 RNP-negative patients in CTD- and SSc-associated PAH. Hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients. In CTD-associated PAH, anti-U1 RNP positivity was associated with decreased mortality in univariable analysis (hazard ratio 0.34 [95% confidence interval 0.18-0.65], P < 0.001). In multivariable analysis, anti-U1 RNP positivity was also associated with decreased mortality (hazard ratio 0.44 [95% confidence interval 0.20-0.97], P = 0.043) independently of age, sex, functional parameters, lung involvement, and hemodynamic parameters. Results were similar in SSc-associated PAH, although the association between anti-U1 RNP positivity and survival did not reach significance in univariable (hazard ratio 0.47 [95% confidence interval 0.22-1.02], P = 0.055) and multivariable (hazard ratio 0.47 [95% confidence interval 0.20-1.11], P = 0.085) analyses. Anti-U1 RNP positivity was associated with distinct clinical characteristics and survival in CTD- and SSc-associated PAH. While hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients, our results suggest that anti-U1 RNP positivity could be a factor protecting against mortality in CTD- and SSc-associated PAH.

Abstract A44: Expression of metabolic genes is associated with prognosis in breast cancer

Abstract Breast cancer is the most common malignancy and is the second leading cause of cancer-related death in American women. Approximately 75% of breast tumors express the oestrogen receptor, which can be targeted for with selective oestrogen receptor modulator such as tamoxifen, or by blocking oestrogen synthesis using aromatase inhibitors. However, approximately a quarter of patients treated for at least five years relapse with the disease within a decade. Many transcriptome studies have been conducted on breast tumor samples with clinical data to generate gene signatures predictive of treatment outcome. While several signatures have been reported, these features tend to be correlated with proliferation and give little information about the underlying tumor biology. An emerging hallmark of cancer is the reprogramming of metabolic networks to meet the demand required for rapid growth of a tumor. Tumors are generally highly glycolytic to meet their energetic requirements, as well as to provide substrates for anabolic reactions necessary for cell growth. However, perturbations in other metabolic pathways that are essential for tumor development and growth remain poorly understood. In this study, we sought to identify and characterise molecular features associated with metabolism that are significantly correlated with breast cancer patient outcome. To achieve this, we performed Cox regression analysis on a training set of microarray gene expression data of 973 oestrogen-receptor positive breast tumors. To identify functional enrichment for the molecular features associated with disease-free survival, gene set enrichment analysis was performed. This analysis revealed a 19-gene signature involved in fatty acid metabolism that showed higher expression to be correlated with good prognosis in the training data (multivariate hazard ratio = 0.51, log-rank p = 2.23e-10). The prognostic performance of this signature was validated on an independent dataset (n=654, multivariate hazard ratio = 0.66, log-rank p = 6.51e-5). Using the online KMplotter software, the fatty acid metabolism signature was found to also be prognostic in both lung cancer (n=1926, univariate hazard ratio = 0.58, log-rank p = 1.1e-16) and gastric cancer (n=593, univariate hazard ratio = 0.73, log-rank p = 0.0012). Based on our bioinformatic findings, we hypothesise that tumors with lowered fatty acid metabolism are more likely to exhibit invasive properties. Current work is focused on understanding how modulating fatty acid metabolism affects tumor biology, and may present a therapeutically tractable process that can be targeted with existing drugs. Citation Format: Abdul Aziz Bin Aiderus, Michael A. Black, Anita K. Dunbier. Expression of metabolic genes is associated with prognosis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A44.

Vaginal Dose Is Associated With Toxicity in Image Guided Tandem Ring or Ovoid-Based Brachytherapy

To calculate vaginal doses during image guided brachytherapy with volume-based metrics and correlate with long-term vaginal toxicity. In this institutional review board-approved study, institutional databases were searched to identify women undergoing computed tomography and/or magnetic resonance-guided brachytherapy at the Duke Cancer Center from 2009 to 2015. All insertions were contoured to include the vagina as a 3-dimensional structure. All contouring was performed on computed tomography or magnetic resonance imaging and used a 0.4-cm fixed brush to outline the applicator and/or packing, expanded to include any grossly visible vagina. The surface of the cervix was specifically excluded from the contour. High-dose-rate (HDR) and low-dose-rate (LDR) doses were converted to the equivalent dose in 2-Gy fractions using an α/β of 3 for late effects. The parameters D0.1cc, D1cc, and D2cc were calculated for all insertions and summed with prior external beam therapy. Late and subacute toxicity to the vagina were determined by the Common Terminology Criteria for Adverse Events version 4.0 and compared by the median and 4th quartile doses, via the log-rank test. Univariate and multivariate hazard ratios were calculated via Cox regression. A total of 258 insertions in 62 women who underwent definitive radiation therapy including brachytherapy for cervical (n=48) and uterine cancer (n=14) were identified. Twenty HDR tandem and ovoid, 32 HDR tandem and ring, and 10 LDR tandem and ovoid insertions were contoured. The median values (interquartile ranges) for vaginal D0.1cc, D1cc, and D2cc were 157.9 (134.4-196.53) Gy, 112.6 (96.7-124.6) Gy, and 100.5 (86.8-108.4) Gy, respectively. At the 4th quartile cutoff of 108 Gy for D2cc, the rate of late grade 1 toxicity at 2 years was 61.2% (95% confidence interval [CI] 43.0%-79.4%) below 108 Gy and 83.9% (63.9%-100%) above (P=.018); grade 2 or greater toxicity was 36.2% (95% CI 15.8%-56.6%) below 108 Gy and 70.7% (95% CI 45.2%-96.2%) above (P=.004); and grade 3 or worse toxicity was 9.9% (95% CI 0.0%-23.6%) below 108 Gy and 30.0% (95% CI 4.7%-55.3%) above (P=.025). This association was maintained on multivariate analysis, independent of covariates such as applicator type, age, and dose rate. Vaginal dose was associated with all grades of vaginal toxicity. Confirmation at other sites using this methodology will be necessary to establish reproducibility; however, the integration of routine calculation of vaginal dose may be warranted.

Abstract 13980: Cardiac Magnetic Resonance Imaging Quantification of Myocardial Ischemia and Necrosis Using a Novel Risk Prediction Model Allows for Better Risk Stratification in Coronary Artery Disease

Background: Cardiac magnetic resonance imaging (CMR) provides information about inducible myocardial ischemia and necrosis in one single examination in coronary artery disease (CAD) patients. Both variables have been shown to correlate with prognosis. However, there is no consensus on how to assess and quantify these two variables. Hypothesis: Objective of the present prospective study in consecutive patients was to provide a simple algorithm for quantification of ischemia and necrosis and to test for risk stratification models. Methods: Patients with known or suspected CAD referred for adenosine-stress CMR were consecutively enrolled from 2003 to 2007. Examination was conducted on a 1.5-T whole-body scanner. Reversible ischemia was diagnosed by adenosine stress first pass perfusion imaging. Myocardial necrosis was assessed by late gadolinium enhancement (LGE). In a semiautomatic approach, extent of reversible ischemia and scar was quantified and reported as percentage of the left ventricle. Primary endpoint was defined as cardiac death, non-fatal myocardial infarction and stroke. Results: The study cohort consisted of 845 patients. Median age was 64 years, 271 patients were women. During a median follow-up period of 3.8 years 61 primary endpoints occurred. Statistical analysis yielded a ≥6% optimal threshold for reversible ischemia to predict a primary endpoint (univariate hazard ratio 4.91, p&lt;.0001). Similarly, thresholds for extent of myocardial necrosis were defined (LGE &gt;15% and ≤33%: univariate hazard ratio 2.75, p&lt;.0001; LGE &gt;33%: univariate hazard ratio 16.27, p&lt;.0001). The risk prediction model containing both, quantified ischemia and necrosis, proved to be superior in comparison to the dichotomous model (ischemia present: yes/no; necrosis present: yes/no) on multivariate testing (increase in χ 2 -values: 45.004 to 61.545; increase in integrated discrimination improvement: .02269 to .03187; net reclassification index for optimal model: .25593, p=.001). Conclusion: CMR cut-off values for quantification of myocardial ischemia (≥6%) and necrosis (&gt;15% and &gt;33%) have been found which allow for better risk stratification in CAD patients. The combination of both has been shown to yield the superior risk stratification model.

Abstract 19925: Novel Pre-implant Characteristics Associated With 12 Month Risk of Gastrointestinal Bleeding Among Patients Supported With Continuous Flow Left Ventricular Assist Device Therapy

Introduction: Continuous-flow Left Ventricular Assisted Device (CF-LVAD) therapy is increasingly utilized for patients with end stage heart failure. Among the most common and unpredictable complications after CF-LVAD is gastrointestinal bleeding (GIB). Hypothesis: We hypothesize that pre-implant characteristics are associated with GIB post-implant of a CF-LVAD. The aim of this analysis is to identify novel pre-implant factors that influence risk of post-implant GIB. Methods: All CF-LVAD implants between January 2006 and December 2014 among patients who survived more than 15 days were included and followed for 12 months. Primary event was GIB and patients were censored at time of re-implant, heart transplant, or death. Student’s t-test was used to compare continuous variables and chi-square test for categorical variables. Cox Proportional Hazards model was used to identify univariate and multivariable models predicting GIB. Results: Among the total 257 patients included, 65 (25.3%) were identified as having a GIB. Baseline differences and their independent univariate hazard ratio (HR) are noted in Table 1. Using stepwise selection and developing a multivariable model, prior GI abnormalities (HR=2.12, p&lt;0.01), prior percutaneous coronary intervention (PCI: HR=2.65, P&lt;0.01) and chronic obstructive pulmonary disease (COPD: HR=1.73, P&lt;0.01) remained statistically significant predictors of GIB (Table 2). Conclusions: We describe novel risk factors (history of GI abnormalities, prior PCI, COPD) as predictors for developing GIB post CF-LVAD implantation. We advocate a closer examination of these risk factors when evaluating patients for CF-LVAD therapy.

Large-volume low apparent diffusion coefficient lesions predict poor survival in bevacizumab-treated glioblastoma patients.

Glioblastomas treated with bevacizumab may develop low-signal apparent diffusion coefficient (low-ADC) lesions, which may reflect increased tumor cellularity or atypical necrosis. The purpose of this study was to examine the relationship between low-ADC lesions and overall survival (OS). We hypothesized that growing low-ADC lesions would be associated with shorter OS. We retrospectively identified 52 patients treated with bevacizumab for the first (n = 42, 81%) or later recurrence of primary glioblastoma, who had low-ADC lesions and 2 post-bevacizumab scans ≤90 days apart. Low-ADC lesion volumes were measured, and normalized 5th percentile histogram low-ADC values were recorded. Using OS as the primary endpoint, semiparametric Cox models were fitted to ascertain univariate and multivariate hazard ratios (HRs) with significance at P = .05. Median OS was 9.1 months (95% CI = 7.2-14.3). At the second post-bevacizumab scan, the volume of the low-ADC lesion (median: 12.94 cm(3)) was inversely associated with OS, with larger volumes predicting shorter OS (HR = 1.014 [95% CI = 1.003-1.025], P = .009). The percent change in low-ADC volume (median: 6.8%) trended toward increased risk of death with growing volumes (P = .08). Normalized 5th percentile low-ADC value and its percent change were not associated with OS (P > .51). Also correlated with shorter OS were the pre-bevacizumab nonenhancing volume (P = .025), the first post-bevacizumab enhancing volume (P = .040), and the second post-bevacizumab enhancing volume (P = .004). The volume of low-ADC lesions at the second post-bevacizumab scan predicted shorter OS. This suggests that low-ADC lesions may be considered important imaging markers and included in treatment decision algorithms.

Mechanical circulatory support and simultaneous heart-kidney transplantation: An outcome analysis

Single-donor simultaneous heart-kidney transplantation (SHKT) can significantly improve the survival of those with advanced heart failure and advanced renal insufficiency. Data on pre-transplant use of mechanical circulatory support (MCS) devices and outcomes after SHKT are limited and conflicting. Using the United Network for Organ Sharing registry data, we evaluated 749 adults undergoing SHKT after January 1, 2000. Patients were categorized into the following groups according to their type of pre-transplant MCS device: none (n = 568), pulsatile-flow left (n = 28), continuous-flow left (n = 68), temporary (n = 12), biventricular (n = 19), total artificial heart (n = 20), and unknown (n = 34). Regression analyses were performed to assess the association between types of MCS and post-transplant outcomes. Pre-transplant MCS was not associated with in-hospital mortality (univariate odds ratio [OR], 1.57; 95% confidence interval [CI], 0.82-2.97; p = 0.170) or post-discharge mortality (univariate hazard ratio, 0.92; 95% CI, 0.58-1.47; p = 0.733). Patients supported with pre-transplant temporary MCS devices were more likely to suffer from serious complications (composite of cardiac or non-cardiac surgeries, stroke, any drug-treated infection, and permanent pacemaker; multivariable adjusted OR, 10.0; 95% CI, 2.77-36.0; p < 0.001) after SHKT. Pre-transplant MCS did not increase risk of post-transplant dialysis (multivariable adjusted OR, 1.19; 95% CI, 0.81-1.75; p = 0.375) or cardiac rejection (univariate OR, 0.71; 95% CI, 0.34-1.51; p = 0.382), and did not prolong the length of hospital stay (≥ 4 weeks; multivariable adjusted OR, 1.05; 95% CI, 0.69-1.59; p = 0.832). Post-transplant dialysis status was a major determinant of adverse in-hospital (multivariable adjusted OR, 6.17; 95% CI, 3.14-12.1; p < 0.001) and post-discharge (multivariable adjusted hazard ratio, 1.56; 95% CI, 1.02-2.39; p = 0.041) mortality after SHKT. In the current transplant era, survival after SHKT in patients with pre-transplant MCS was equivalent to that of conventional SHKT. Pre-transplant dialysis, and not MCS status, determined the need for post-SHKT dialysis, which in-turn was a major risk factor for in-hospital and long-term mortality.

Primary tumour standardised uptake value is prognostic in nonsmall cell lung cancer: a multivariate pooled analysis of individual data.

(18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma.

High hemoglobin A1c variability is associated with early risk of microalbuminuria in children with T1D.

To test the hypothesis that HbA1c variability, as measured by standard deviation (SD), is associated with increased risk for incident microalbuminuria and persistent microalbuminuria in pediatric type 1 diabetes (T1D). A retrospective analysis using data from electronic health records was performed on 1195 patients from a pediatric diabetes clinic network in the Midwest USA from 1993 to 2009 with ≥1 yr of T1D, ≥4 total HbA1c values, ≥2 HbA1c values/yr, ≥1 urine microalbumin. Microalbuminuria, the main outcome was defined as albumin excretion rate ≥20 mcg/min or 2 of 3 consecutive urine microalbumin/creatinine ≥30 mg/gm. Patients who had persistently high microalbumin or who were treated with an angiotensin-converting-enzyme inhibitor within 1 yr were considered to have persistent microalbuminuria. Sex, race, age, diagnosis age, and duration were covariates. Median numbers of per-patient HbA1c and microalbumin results were 14 and 3, respectively. Median intrapersonal mean HbA1c and SD were 8.62% (70.72 mol/mol) and 1.47% (16.07 mmol/mol), respectively. The median interquartile range (IQR) of diagnosis age was 9.4 yr (6.26-12.02) and diabetes duration was 4.97 yr (2.93-7.64). A total of 172 patients (14.4%) developed microalbuminuria; 55 (4.6%) had persistent microalbuminuria. Patients with higher SD of HbA1c had shorter time to microalbuminuria. In time-dependent Cox Proportional Hazard models, updated SD of HbA1c was significantly associated with microalbuminuria [univariate hazard ratio (HR) 1.48 (1.25-1.76); multivariable HR 1.28 (1.04-1.58)], whereas updated mean HbA1c was not [univariate HR 1.08 (0.97-1.22); multivariable HR 1.05 (0.92-1.2)]. Patients with persistent microalbuminuria had similar HRs. HbA1c variability is independently associated with development of microalbuminuria in children with T1D, highlighting the importance of maintaining stable glycemic control in pediatric patients.

Combination chemotherapy of gemcitabine and vinorelbine for pretreated non-small-cell lung cancer: a retrospective study.

BackgroundAdvanced non-small-cell lung cancer (NSCLC) eventually progresses after first-line chemotherapy, and usually requires salvage treatment. Although neither gemcitabine nor vinorelbine is approved as a candidate drug in the second- or further-line for NSCLC, they can be alternative drugs in terms of anti-tumor effects and toxicities. Actually, in our institution, we often use a combination of these two anti-tumor drugs in our daily practice.MethodsWe retrospectively reviewed 85 patients with advanced NSCLC who had received combination chemotherapy of gemcitabine and vinorelbine after a platinum-based regimen from June 2007 to June 2014 in Osaka Police Hospital, and performed Cox proportional hazard analyses in order to detect predictive factors for progression-free survival (PFS).ResultsPatient characteristics included a mean age of 65.5 years, 56 males, 54 adenocarcinoma, 53 European Clinical Oncology Group performance status 0–1. Thirteen and 35 patients received the study treatment as the second- and third-line treatment, respectively. The overall response rate, disease control rate, PFS, and overall survival were 4.7% (95% confidence interval 1.3%–11.6%), 30.6% (21.0%–41.5%), 2.1 months (1.7–2.8 months), and 6.9 months (5.0–11.0 months). Twenty-one and six patients experienced grade 4 neutropenia and febrile neutropenia, respectively. European Clinical Oncology Group performance status 0–1 was detected as a factor predicting longer PFS by univariate (hazard ratio, 1.63; 95% confidence interval, 1.28–2.08; P<0.001) and multivariate (1.65, 1.27–2.14, P<0.001) analyses.ConclusionThis combination was ineffective and harmful to pretreated patients with NSCLC. We do not recommend this regimen as a later-line treatment option.

Gender Disparity and Mutation Burden in Metastatic Melanoma.

Gender differences in melanoma incidence and outcome have been consistently observed but remain biologically unexplained. We hypothesized that tumors are genetically distinct between men and women and analyzed the mutation spectra in 266 metastatic melanomas (102 women and 164 men) from The Cancer Genome Atlas (TCGA). We found a statistically significantly greater burden of missense mutations among men (male median 298 vs female median = 211.5; male-to-female ratio [M:F] = 1.85, 95% confidence interval [CI] = 1.44 to 2.39). We validated these initial findings using available data from a separate melanoma exome cohort (n = 95) and found a similar increase in missense mutations among men (male median 393 vs female median 259; M:F = 1.59, 95% CI = 1.12 to 2.27). In addition, we found improved survival with increasing log-transformed missense mutation count (univariate hazard ratio = 0.82, 95% CI = 0.69 to 0.98) for TCGA samples. Our analyses demonstrate for the first time a gender difference in mutation burden in cutaneous melanoma.

Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status.

Experimental models implicate protease activated receptors (PARs) as important sensors of the proteolytic tumor microenvironment during breast cancer development. However, the role of the major PARs, PAR-1 and PAR-2, in human breast tumors remains to be elucidated. Here, we have investigated how PAR-1 and PAR-2 protein expression correlate with established clinicopathological variables and patient outcome in a well-characterized cohort of 221 breast cancer patients. Univariable and multivariable hazard ratios (HR) were estimated by the Cox proportional hazards model, distant disease-free survival (DDFS) and overall survival by the Kaplan–Meier method, and survival in different strata was determined by the log-rank test. Associations between PARs and clinicopathological variables were analyzed using Pearson’s χ2-test. We find that PAR-2 associates with DDFS (HR = 3.1, P = 0.003), whereas no such association was found with PAR-1 (HR = 1.2, P = 0.6). Interestingly, the effect of PAR-2 was confined to the ER-positive sub-group (HR = 5.5, P = 0.003 vs. HR = 1.2 in ER-negative; P = 0.045 for differential effect), and PAR-2 was an independent prognostic factor specifically in ER-positive tumors (HR = 3.9, P = 0.045). On the contrary, PAR-1 correlated with worse prognosis specifically in the ER-negative group (HR = 2.6, P = 0.069 vs. HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect). This study provides novel insight into the respective roles of PAR-1 and PAR-2 in human breast cancer and suggests a hitherto unknown association between PARs and ER signaling that warrants further investigation.

Accumulated Delivered Dose Response of Stereotactic Body Radiation Therapy for Liver Metastases

To determine whether the accumulated dose using image guided radiation therapy is a stronger predictor of clinical outcomes than the planned dose in stereotactic body radiation therapy (SBRT) for liver metastases. From 2003 to 2009, 81 patients with 142 metastases were treated in institutional review board-approved SBRT studies (5-10 fractions). Patients were treated during free breathing (with or without abdominal compression) or with controlled exhale breath-holding. SBRT was planned on a static exhale computed tomography (CT) scan, and the minimum planning target volume dose to 0.5 cm(3) (minPTV) was recorded. The accumulated minimum dose to the 0.5 cm(3) gross tumor volume (accGTV) was calculated after performing dose accumulation from exported image guided radiation therapy data sets registered to the planning CT using rigid (2-dimensional MV/kV orthogonal) or deformable (3-dimensional/4-dimensional cone beam CT) image registration. Univariate and multivariate Cox regression models assessed the factors influencing the time to local progression (TTLP). Hazard ratios for accGTV and minPTV were compared using model goodness-of-fit and bootstrapping. Overall, the accGTV dose exceeded the minPTV dose in 98% of the lesions. For 5 to 6 fractions, accGTV doses of >45 Gy were associated with 1-year local control of 86%. On univariate analysis, the cancer subtype (breast), smaller tumor volume, and increased dose were significant predictors for improved TTLP. The dose and volume were uncorrelated; the accGTV dose and minPTV dose were correlated and were tested separately on multivariate models. Breast cancer subtype, accGTV dose (P<.001), and minPTV dose (P=.02) retained significance in the multivariate models. The univariate hazard ratio for TTLP for 5-Gy increases in accGTV versus minPTV was 0.67 versus 0.74 (all patients; 95% confidence interval of difference 0.03-0.14). Goodness-of-fit testing confirmed the accGTV dose as a stronger dose-response predictor than the minPTV dose. The accGTV dose is a better predictor of TTLP than the minPTV dose for liver metastasis SBRT. The use of modern image guided radiation therapy in future analyses of dose-response outcomes should increase the concordance between the planned and delivered doses.

Septic arthritis in gout patients: a population-based cohort study.

To evaluate the association of incident gout with the risk of incident septic arthritis in a general population context. We investigated the association of incident gout with the risk of incident septic arthritis using the Health Improvement Network, a computerized medical record database from general practices in the UK. We conducted a cohort analysis of the risk of an incident septic arthritis diagnosis among adults with incident gout compared with up to five non-gout individuals matched by age, sex, date of study entry and enrolment year. We performed Cox proportional hazard regression models to adjust for lifestyle variables, physician visits, comorbidities and medication use. We identified 72 073 incident gout patients and 358 342 matched non-gout patients. The incidence rates of a septic arthritis diagnosis were 0.24 cases and 0.09 cases per 1000 person-years in the gout and comparison cohorts, respectively. Matched univariate and multivariate hazard ratios of a septic arthritis diagnosis were 2.82 (95% CI 2.15, 3.71) and 2.60 (95% CI 1.93, 3.51), respectively. The association persisted among subgroups stratified by sex, age group (<75 and ≥75) and socio-economic deprivation level. This general population-based study suggests that gout is associated with an increased likelihood of septic arthritis.

Does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer?

The ability of perineural invasion (PNI) in radical prostatectomy (RP) specimens to predict biochemical recurrence (BCR) is unclear. This study investigates this controversial question in a large cohort. A retrospective analysis was undertaken of prospectively collected data from 1497 men who underwent RP (no neoadjuvant therapy) for clinically localized prostate cancer. The association of PNI at RP with other clinicopathological parameters was evaluated. The correlation of clinicopathological factors and BCR (defined as prostate-specific antigen [PSA] >0.2 ng/mL) was investigated with univariable and multivariable Cox regression analysis in 1159 men. PNI-positive patients were significantly more likely to have a higher RP Gleason score, pT3 disease, positive surgical margins, and greater cancer volume (p < 0.0005). The presence of PNI significantly correlated with BCR on univariable (hazard ratio 2.30, 95% confidence interval 1.50-3.55, p < 0.0005), but not multivariable analysis (p = 0.602). On multivariable Cox regression analysis the only independent prognostic factors were preoperative PSA, RP Gleason score, pT-stage, and positive surgical margin status. These findings are limited by a relatively short follow-up time and retrospective study design. PNI at RP is not an independent predictor of BCR. Therefore, routine reporting of PNI is not indicated. Future research should be targeted at the biology of PNI to increase the understanding of its role in prostate cancer progression.

Predictors of reoperation-free survival following decompression-alone lumbar spine surgery for on-the-job injuries

IntroductionWorkers’ compensation patients are known to be associated with inferior outcomes following lumbar surgery. We investigated demographics and clinical characteristics between the reoperative and non-reoperative group of patients undergoing decompression-alone lumbar surgery (discectomy and/or laminectomy) for on-the-job injuries (OJI) at our institute, and evaluated its possible impact on the reoperation-free survival (RFS). MethodsA retrospective analysis of patients undergoing lumbar surgery for OJI between 2003 through 2010 by a single surgeon (A.N.) was performed. A comparison of baseline clinical and demographic parameters between the two groups was compared using Fisher's exact test for the categorical variables and the independent t-test (2-tailed) for the continuous variables. Overall, RFS was presented in Kaplan–Meier curves and the RFS difference was compared using log-rank (Mantel–Cox) test. Cox proportional hazard model was used for the univariate and multivariate analysis and hazard ratios with 95% confidence intervals were reported. ResultsAbout 92 patients with mean age 48.07±10.10 years and mean follow-up of 36.4 (range 24.3–66.0) months were included. About 38 (41.3%) patients underwent reoperation for failed decompression-alone procedures whereas the non-reoperative cohort comprises 54 (58.7%) patients. Female gender (p=0.015) and history of previous surgery (p=0.05) were associated with a higher chance of reoperation. Majority of the reoperations (20/38, 52.6%) were performed within the first 2 years, with a RFS at the end of 2 years being 78.3% (n=72) and 58.9% (n=53) at 5 years. Cox-regression analysis did not demonstrate any influence of patients and treatment-related factors on the RFS. ConclusionThere is a substantial risk of redo surgeries following decompression-alone lumbar procedures for OJI. As patient and treatment-related factors did not influence the reoperation rates and RFS in this study, it appears that workman compensation status of patients is inherently associated with poor outcomes following spine surgeries.