Understanding Treatment Response in Individual Profiles of Men with Prostatic Enlargement at Risk of Progression.

BACKGROUND: It is unclear how cumulative multivariable effects of clinically relevant covariates impact response to pharmacological treatments for lower urinary tract symptoms (LUTS)/benign prostatic enlargement (BPE). OBJECTIVE: To develop models to predict treatment response in terms of International Prostate Symptom Score (IPSS) and the risk of acute urinary retention (AUR) or BPE-related surgery, based on large data sets and using as predictors baseline characteristics that commonly define the risk of disease progression. DESIGN, SETTING, AND PARTICIPANTS: A total of 9167 patients with LUTS/BPE at risk of progression in three placebo-controlled dutasteride trials and one comparing dutasteride, tamsulosin, and dutasteride + tamsulosin combination therapy (CT) were included in the analysis to predict response to placebo up to 24 mo and active treatment up to 48 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictors included age, IPSS, total prostate volume (PV), maximum urinary flow rate (Qmax), prostate-specific antigen, postvoid residual urine (PVR), α-blocker usage within 12 mo, and randomised treatment. A generalised least-squares model was developed for longitudinal IPSS and a Cox proportional-hazards model for time to first AUR/surgery. RESULTS AND LIMITATIONS: The vast majority of patients benefit from dutasteride or CT when compared with tamsulosin alone. The predicted IPSS improvement with dutasteride or CT increased with greater PV and severity of symptoms at baseline. The tamsulosin effect was lower with greater baseline PV and tended to decrease over time. Predicted AUR/surgery risk was greater with tamsulosin versus CT or dutasteride; this risk increased with larger PV, higher PVR, and lower Qmax (all at baseline). An educational interactive web-based tool facilitates visualisation of the results (www.bphtool.com). Limitations include: the placebo and active-treatment predictions are from different studies, the lack of similar studies for external validation, and the focus on a population at risk of progression from the 4-yr CombAT study. CONCLUSIONS: Predictive modelling based on large data sets and visualisation of the risk for individual profiles can improve our understanding of how risk factors for disease progression interact and affect response to different treatments, reinforcing the importance of an individualised approach for LUTS/BPE management. PATIENT SUMMARY: We used data from previous studies to develop statistical models for predicting how men with lower urinary tract symptoms or benign prostate enlargement and at risk of disease complications respond to certain treatments according to their individual characteristics.

Outcomes following formation of a dedicated pediatric liver transplant anesthesia team.

BACKGROUND: Given the complex nature of liver transplant surgery, adult centers typically use a dedicated liver transplant anesthesia team, which has improved patient outcomes. AIMS: Our goal was to determine whether a dedicated pediatric liver transplant anesthesia team was associated with improved patient outcomes. METHODS: This retrospective cohort study analyzed patients who underwent liver transplantation from April 2013 to September 2020 at St. Louis Children's Hospital. The general group (April 2013-December 2016) was compared with the liver group (January 2017-September 2020). Outcomes measured included cases per anesthesiologist, early extubation, ventilator days, fluid and blood administration, postoperative events, and intensive care unit and hospital length of stay (LOS). RESULTS: Patients in both groups had similar demographics. The average number of cases/anesthesiologist/year was 2.9 times higher in the liver group (mean (SD) general 0.7 (0.5), liver 2.0 (0.6), and difference in mean [95% CI] 1.3 [0.8, 1.8]). The rate of extubation in the operating room was higher for patients in the liver group (general 56%, liver 80%, and difference in proportion [95% CI] 24.7 [7.0, 42.4]), while the number of ventilator days was lower (mean (SD) general 2.1 (4.4), liver 1.1 (3.6), and difference in proportion [95%CI] -0.9 [-2.6, 0.7]). Colloid administration was higher in the liver group (mean (SD) general 23.9 (14.5) ml/kg, liver 48.4 (37.7) ml/kg, and difference in mean [95% CI] 24.6 [12.7, 36.4]), while fresh frozen plasma administration was lower in the liver group (mean (SD) general 15.3 (23.9) ml/kg, liver 6.2 (14) ml/kg, and difference in mean [95% CI] -9.0 [-16.8, -1.3]). There were no significant differences between the groups in postoperative events including blood product transfusions, vasopressor use, and thromboses, or in the intensive care unit and hospital LOS. CONCLUSIONS: The liver group was associated with increased early extubations, decreased ventilator days, and decreased fresh frozen plasma use.

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

Endoscopic Versus Open Repair for Craniosynostosis in Infants Using Propensity Score Matching to Compare Outcomes: A Multicenter Study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The North American Pediatric Craniofacial Collaborative Group (PCCG) established the Pediatric Craniofacial Surgery Perioperative Registry to evaluate outcomes in infants and children undergoing craniosynostosis repair. The goal of this multicenter study was to utilize this registry to assess differences in blood utilization, intensive care unit (ICU) utilization, duration of hospitalization, and perioperative complications between endoscopic-assisted (ESC) and open repair in infants with craniosynostosis. We hypothesized that advantages of ESC from single-center studies would be validated based on combined data from a large multicenter registry. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. We analyzed 1382 infants younger than 12 months undergoing open (anterior and/or posterior cranial vault reconstruction, modified-Pi procedure, or strip craniectomy) or endoscopic craniectomy. The primary outcomes included transfusion data, ICU utilization, hospital length of stay, and perioperative complications; secondary outcomes included anesthesia and surgical duration. Comparison of unmatched groups (ESC: N = 311, open repair: N = 1071) and propensity score 2:1 matched groups (ESC: N = 311, open repair: N = 622) were performed by conditional logistic regression analysis. RESULTS: Imbalances in baseline age and weight are inherent due to surgical selection criteria for ESC. Quality of propensity score matching in balancing age and weight between ESC and open groups was assessed by quintiles of the propensity scores. Analysis of matched groups confirmed significantly reduced utilization of blood (26% vs 81%, P < .001) and coagulation (3% vs 16%, P < .001) products in the ESC group compared to the open group. Median blood donor exposure (0 vs 1), anesthesia (168 vs 248 minutes) and surgical duration (70 vs 130 minutes), days in ICU (0 vs 2), and hospital length of stay (2 vs 4) were all significantly lower in the ESC group (all P < .001). Median volume of red blood cell administered was significantly lower in ESC (19.6 vs 26.9 mL/kg, P = .035), with a difference of approximately 7 mL/kg less for the ESC (95% confidence interval for the difference, 3-12 mL/kg), whereas the median volume of coagulation products was not significantly different between the 2 groups (21.2 vs 24.6 mL/kg, P = .73). Incidence of complications including hypotension requiring treatment with vasoactive agents (3% vs 4%), venous air embolism (1%), and hypothermia, defined as <35°C (22% vs 26%), was similar between the 2 groups, whereas postoperative intubation was significantly higher in the open group (2% vs 10%, P < .001). CONCLUSIONS: This multicenter study of ESC versus open craniosynostosis repair represents the largest comparison to date. It demonstrates striking advantages of ESC for young infants that may result in improved clinical outcomes, as well as increased safety.

Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time.

BACKGROUND: Extracellular volume (ECV) by T1 mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus-only ECV). For large ECV, the bolus-only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis. PURPOSE: To characterize the relationship between the bolus-only and current gold-standard infusion ECV in patients with amyloidosis. STUDY TYPE: Bolus-only and infusion ECV were prospectively measured. POPULATION: In all, 186 subjects with systemic amyloidosis attending our clinic and 23 subjects with systemic amyloidosis who were participating in an open-label, two-part, dose-escalation, phase 1 trial. FIELD STRENGTH: Avanto 1.5T, Siemens Medical Solutions, Erlangen, Germany. ASSESSMENT: Bolus-only and infusion ECV were measured in all subjects using shortened modified Look-Locker inversion recovery (ShMOLLI) T1 mapping sequence. STATISTICAL TESTS: Pearson correlation coefficient (r); Bland-Altman; receiver operating characteristic (ROC) curve analysis. Linear regression model with a fractional polynomial transformation. RESULTS: The difference between the bolus-only and infusion myocardial ECV increased as the average of the two measures increased, with the bolus-ECV measuring higher. For an average ECV of 0.4, the difference was 0.013. The 95% limits of agreement for the two methods, after adjustment for the bias, were ±0.056. However, cardiac diagnostic accuracy was comparable (bolus-only vs. infusion ECV area under the curve [AUC] = 0.839 vs. 0.836), as were correlations with other clinical cardiac measures, and, in the trial patients, the ability to track changes in the liver/spleen with therapy. DATA CONCLUSION: In amyloidosis, with large ECVs, the bolus-only technique reads higher than the infusion technique, but clinical performance by any measure is the same. Given the work-flow advantages, these data suggest that the bolus-only approach might be acceptable for amyloidosis, and might support its use as a surrogate endpoint in future clinical trials. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1677-1684.

Preoperative malnutrition is associated with increased mortality and adverse outcomes after paediatric cardiac surgery.

BACKGROUND: Malnutrition is common in children with CHD and is likely to place them at an increased risk for adverse surgical outcomes. We sought to evaluate the impact of preoperative malnutrition on outcomes after paediatric cardiac surgery. METHODS: We conducted a retrospective analysis of patients from age 0 to 5 years undergoing cardiac surgery at Seattle Children's Hospital from 2006 to 2015. We used regression modelling to examine the impact of malnutrition on surgical outcomes. RESULTS: We found a non-linear relationship between low height-for-age and weight-for-age z-scores and mortality after surgery. In the range of z-score ⩽-2, each additional unit decrease in height-for-age or weight-for-age z-score was associated with a 2.9 or 2.1% increased risk for mortality, respectively. Each unit decrease in height-for-age z-score was associated with a 1.2% increased risk for cardiac arrest, 1.1% increased risk for infection, and an average of 1.7 additional hours of mechanical ventilation, 6 hours longer ICU stay, and 13 hours longer hospital stay. Each unit decrease in weight-for-age z-score was associated with a 0.7% increased risk for cardiac arrest, 0.8% increased risk for infection, and an average of 1.9 additional hours of mechanical ventilation and 5.3 additional hours of ICU stay. CONCLUSIONS: This study is unique in demonstrating a significant association between malnutrition and 30-day mortality and other adverse outcomes after paediatric cardiac surgery in a mixed population of CHD patients. By evaluating nutritional status as a continuous variable, we were able to clearly distinguish the point at which malnutrition begins to affect mortality.

Perioperative Outcomes and Management in Pediatric Complex Cranial Vault Reconstruction: A Multicenter Study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The Pediatric Craniofacial Collaborative Group established the Pediatric Craniofacial Surgery Perioperative Registry to elucidate practices and outcomes in children with craniosynostosis undergoing complex cranial vault reconstruction and inform quality improvement efforts. The aim of this study is to determine perioperative management, outcomes, and complications in children undergoing complex cranial vault reconstruction across North America and to delineate salient features of current practices. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. Data extracted included demographics, perioperative management, length of stay, laboratory results, and blood management techniques employed. Complications and outlier events were described. Outcomes analyzed included total blood donor exposures, intraoperative and perioperative transfusion volumes, and length of stay outcomes. RESULTS: One thousand two hundred twenty-three cases were analyzed: 935 children aged less than or equal to 24 months and 288 children aged more than 24 months. Ninety-five percent of children aged less than or equal to 24 months and 79% of children aged more than 24 months received at least one transfusion. There were no deaths. Notable complications included cardiac arrest, postoperative seizures, unplanned postoperative mechanical ventilation, large-volume transfusion, and unplanned second surgeries. Utilization of blood conservation techniques was highly variable. CONCLUSIONS: The authors present a comprehensive description of perioperative management, outcomes, and complications from a large group of North American children undergoing complex cranial vault reconstruction. Transfusion remains the rule for the vast majority of patients. The occurrence of numerous significant complications together with large variability in perioperative management and outcomes suggest targets for improvement.

Making the Case for Palliative Care at the System Level: Outcomes Data.

BACKGROUND: A recent trend in health care is to integrate palliative care (PC) programs across multiple hospitals to reduce variation, improve quality, and reduce cost. OBJECTIVE: The study objective was to demonstrate the benefits of PC for a system. METHODS: The study was a descriptive study using retrospective medical records in seven federated hospitals where PC developed differently before system integration. Measured were length of stay (LOS), mortality, readmissions, saved intensive care unit (ICU) days, cost avoidance, and hospice referrals. RESULTS: PC services within the first 48 hours of admission demonstrate a shorter LOS (5.08 days), reduced costs 40% ($2,362 per day), and decreased mortality (1.01 versus 1.10) for one hospital. Readmissions at 30, 60, and 90 days after a PC consult decreased (61.5%, 47.0%, and 42.1%, respectively). Annual pre- and postprogram referrals to hospice increased (65 to 107). Using modified matched pairs, LOS of PC patients seen within 48 hours of admission average 1.67 days less compared to non-PC patients. LOS for ICU patients with PC services in the ICU within the first 48 hours decreased by 1.12 days. Overall cost avoidance was 1.5 times total cost for PC programs systemwide. One pilot project using a full-time physician in the ICU reduced cost more than $600,000, with 315 saved ICU days, annualized. Systemwide, 69.3% of all referrals to hospice were made by the PC service. CONCLUSION: Early involvement of PC services emerged as advantageous to the net benefit. Given that health care's changing landscape will increasingly include bundled payment and risk holding strategies to improve quality and reduce cost in health care systems, systemwide PC will play a vital role.

Perioperative and Anesthetic Considerations in Ebstein's Anomaly.

Ebstein's anomaly is a complex and heterogeneous form of congenital heart disease characterized by malformation and apical displacement of the tricuspid valve leaflets. Patients may present at any time from the neonatal period to adulthood with symptoms ranging from cardiac failure and cyanosis to paroxysmal arrhythmias. Depending on the timing of presentation, various surgical options are available for the management of symptomatic patients. This review will discuss the perioperative and anesthetic management of patients with Ebstein's anomaly with reference to the more common surgical approaches.

Large-volume vitrification of human biopsied and non-biopsied blastocysts: a simple, robust technique for cryopreservation.

PURPOSE: To evaluate the transition from a proven slow-cooling cryopreservation method to a commercial large-volume vitrification system for human blastocysts. METHODS: Retrospective analysis of de-identified laboratory and clinical data from January 2012 to present date for all frozen embryo replacement (FET) cycles was undertaken. Cryopreservation of trophectoderm-biopsied or non-biopsied blastocysts utilized during this time period was logged as either slow-cooling, small-volume vitrification, or large-volume vitrification. Blastocyst survival post-warm or post-thaw, clinical pregnancy following FET, and implantation rates were identified for each respective cryopreservation method. RESULTS: Embryo survival was highest for large-volume vitrification compared to micro-volume vitrification and slow-cooling; 187/193 (96.9 %), 27/32 (84.4 %), and 244/272 (89.7 %), respectively. Survival of biopsied and non-biopsied blastocysts vitrified using the large-volume system was 105/109 (96.3 %) and 82/84 (97.6 %), respectively. Survival for micro-volume biopsied and non-biopsied blastocysts was 16/30 (83.3 %) and 2/2 (100.0 %) respectively. Slow-cooling post-thaw embryo survival was 272/244 (89.7 %). Clinical pregnancy and implantation rates outcomes for non-biopsied embryos were similar between large-volume and slow-cooling cryopreservation methods, 18/39 (46.2 %) clinical pregnancy and 24/82 (29.3 %) implantation/embryo, and 52/116 (44.8 %) clinical pregnancy and 67/244 (27.5 %) implantation/embryo, respectively. Comparing outcomes for biopsied embryos, clinical pregnancy and implantation rates were 39/67 (58.2 %) clinical pregnancy and 50/105 (47.6 %) implantation/embryo and 4/16 (25 %) clinical pregnancy and 6/25 (24.0 %) implantation/embryo, respectively. CONCLUSIONS: The LifeGlobal large-volume vitrification system proved to be very reliable, simple to learn and implement in the laboratory. Clinically large-volume vitrification was as, or more effective compared to slow-cooling cryopreservation in terms of recovery of viable embryos in this laboratory.

Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection.

PURPOSE: The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial. EXPERIMENTAL DESIGN: ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial). RESULTS: Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm. CONCLUSIONS: This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts.

Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patients with delayed graft function following renal transplantation.

Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67-0.85) for ACY-1, 0.9 (0.84-0.95) for cystatin C, and 0.93 (0.88-0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor-brain-dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation.

Race/ethnicity, education, and treatment parameters as moderators and predictors of outcome in binge eating disorder.

OBJECTIVE: Binge eating disorder (BED) is prevalent among individuals from minority racial/ethnic groups and among individuals with lower levels of education, yet the efficacy of psychosocial treatments for these groups has not been examined in adequately powered analyses. This study investigated the relative variance in treatment retention and posttreatment symptom levels accounted for by demographic, clinical, and treatment variables as moderators and predictors of outcome. METHOD: Data were aggregated from 11 randomized, controlled trials of psychosocial treatments for BED conducted at treatment sites across the United States. Participants were N = 1,073 individuals meeting criteria for BED including n = 946 Caucasian, n = 79 African American, and n = 48 Hispanic/Latino participants. Approximately 86% had some higher education; 85% were female. Multilevel regression analyses examined moderators and predictors of treatment retention, Eating Disorder Examination (EDE) global score, frequency of objective bulimic episodes (OBEs), and OBE remission. RESULTS: Moderator analyses of race/ethnicity and education were nonsignificant. Predictor analyses revealed African Americans were more likely to drop out of treatment than Caucasians, and lower level of education predicted greater posttreatment OBEs. African Americans showed a small but significantly greater reduction in EDE global score relative to Caucasians. Self-help treatment administered in a group showed negative outcomes relative to other treatment types, and longer treatment was associated with better outcome. CONCLUSIONS: Observed lower treatment retention among African Americans and lesser treatment effects for individuals with lower levels of educational attainment are serious issues requiring attention. Reduced benefit was observed for shorter treatment length and self-help administered in groups.

A comparison of the analytical performance of five commercially available assays for neutrophil gelatinase-associated lipocalin using urine.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for acute kidney injury that is beginning to be used in clinical practice in addition to research studies. The current study describes an independent validation and comparison of five commercially available NGAL assays, focusing on urine samples. This is an essential step in the translation of this marker to clinical use in terms of allowing valid inter-study comparison and generation of robust results. METHODS: Two CE (Conformité Européenne)-marked assays, the NGAL Test (BioPorto) on Siemens ADVIA(®) 1800 and the ARCHITECT Urine NGAL assay on i2000SR (Abbott Laboratories), and three research-use-only (RUO) ELISAs (R&D Systems, Hycult and BioPorto) were evaluated. Imprecision, parallelism, recovery, selectivity, limit of quantitation (LOQ), vulnerability to interference and hook effect were assessed and inter-assay agreement was determined using 68 urine samples from patients with various renal diseases and healthy controls. RESULTS: The Abbott and R&D Systems assays demonstrated satisfactory performance for all parameters tested. However for the other three assays evaluated, problems were identified with LOQ (BioPorto/ADVIA(®)), parallelism (BioPorto ELISA) or several parameters (Hycult). Between-method agreement varied with the Hycult assay in particular being markedly different and highlighting issues with standardization and form of NGAL measured. CONCLUSIONS: Variability exists between the five NGAL assays in terms of their performance and this should be taken into account when interpreting results from the various clinical or research studies measuring urinary NGAL.

Proteomic studies of urinary biomarkers for prostate, bladder and kidney cancers.

Urine is an ideal body fluid for the detection of protein markers produced by urological cancers as it can be sampled noninvasively and contains secreted and directly shed proteins from the prostate, bladder and kidney. Major challenges of working with urine include high inter-individual and intra-individual variability, low protein concentration, the presence of salts and the dynamic range of protein expression. Despite these challenges, significant progress is being made using modern proteomic methods to identify and characterize protein-based markers for urological cancers. The development of robust, easy-to-use clinical tests based on novel biomarkers has the potential to impact upon diagnosis, prognosis and monitoring and could revolutionize the treatment and management of these cancers.

Measuring carbonic anhydrase IX as a hypoxia biomarker: differences in concentrations in serum and plasma using a commercial enzyme-linked immunosorbent assay due to influences of metal ions.

BACKGROUND: There is increasing interest in measuring the soluble forms of carbonic anhydrase IX (CA IX) in blood as a marker of hypoxia for prognostic purposes or for predictive use in therapeutic trials in various cancers. Following our initial observations of marked differences in the measured concentrations of CA IX in EDTA plasma versus serum, we sought to investigate these further in order to determine their effects on results in published studies and to ensure accurate measurement in future studies. METHODS: Serum and EDTA plasma samples from healthy controls and patients with renal cancer were used in the validation of two commercially available enzyme-linked immunosorbent assays (ELISAs) for CA IX with examination of recovery, parallelism and specificity and comparison of paired plasma and serum. RESULTS: Successful validation of one of the ELISAs was not achieved with particular problems with parallelism and marked differences in measured CA IX concentrations between EDTA plasma and serum. This appeared to be due to a metal ion-dependent epitope on CA IX recognized by the detection antibody in this assay. The other commercially available ELISA examined was successfully validated and showed no difference in CA IX between EDTA plasma and serum. CONCLUSIONS: These results have important consequences for published studies using this assay where the conclusions drawn from the measurements made may be invalid. This study highlights the need for stringent validation of commercially available assays, including examination of various sample types, before use in research studies.

Prospective associations among cereal intake in childhood and adiposity, lipid levels, and physical activity during late adolescence.

Cereal consumption is a common dietary behavior that has been associated with positive health outcomes. The objective of this study was to examine prospective associations between cereal intake in childhood and percent body fat, waist-to-hip ratio, lipid levels, and physical activity during late adolescence. In this longitudinal investigation (data collected 1987-1997), data were analyzed for the 2,379 girls who participated in the 10-year National Heart, Lung, and Blood Institute Growth and Health Study. The cumulative percent of days that each girl consumed cereal during childhood (based on 3-day food diaries collected during six study visits between ages 11.5 and 18.6 years) was examined in relation to percent body fat, waist-to-hip ratio, lipid levels, and physical activity measured at age 18.6 years. Results indicated that nearly all girls (90.1%) reported eating cereal and 18.7% reported eating cereal on half or more of the days reported in the food diaries. Girls who ate cereal on a greater percentage of days during childhood had lower percent body fat and total cholesterol, and were more likely to exhibit high levels of physical activity and less television viewing during Study Year 10 (P values<0.05). Further research should explore lifestyle issues related to cereal consumption.