Cross-Canada differences in early-stage breast cancer treatment and acute-care use.

Background: Chemotherapy has improved outcomes in early-stage breast cancer, but treatment practices vary, and use of acute care is common. We conducted a pan-Canadian study to describe treatment differences and the incidence of emergency department visits (edvs), edvs leading to hospitalization (edvhs), and direct hospitalizations (hs) during adjuvant chemotherapy. Methods: The cohort consisted of women diagnosed with early-stage breast cancer (stages i-iii) during 2007-2012 in British Columbia, Manitoba, Ontario, or Nova Scotia who underwent curative surgery. Parallel provincial analyses were undertaken using linked clinical, registry, and administrative databases. The incidences of edvs, edvhs, and hs in the 6 months after treatment initiation were examined for patients treated with adjuvant chemotherapy. Results: The cohort consisted of 50,224 patients. The proportion of patients who received chemotherapy varied by province, with Ontario having the highest proportion (46.4%), and Nova Scotia, the lowest proportion (38.0%). Age, stage, receptor status, comorbidities, and geographic location were associated with receipt of chemotherapy in all provinces. Ontario had the highest proportion of patients experiencing an edv (36.1%), but the lowest proportion experiencing h (6.4%). Conversely, British Columbia had the lowest proportion of patients experiencing an edv (16.0%), but the highest proportion experiencing h (26.7%). The proportion of patients having an edvh was similar across provinces (13.9%-16.8%). Geographic location was associated with edvs, edvhs, and hs in all provinces. Conclusions: Intra- and inter-provincial differences in the use of chemotherapy and acute care were observed. Understanding variations in care can help to identify gaps and opportunities for improvement and shared learnings.

ORE identifies extreme expression effects enriched for rare variants.

MOTIVATION: Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. RESULTS: We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. AVAILABILITY AND IMPLEMENTATION: ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The role of scientific evidence in decisions to adopt complex innovations in cancer care settings: a multiple case study in Nova Scotia, Canada.

BACKGROUND: Health care delivery and outcomes can be improved by using innovations (i.e., new ideas, technologies, and practices) supported by scientific evidence. However, scientific evidence may not be the foremost factor in adoption decisions and is rarely sufficient. The objective of this study was to examine the role of scientific evidence in decisions to adopt complex innovations in cancer care. METHODS: Using an explanatory, multiple case study design, we examined the adoption of complex innovations in five purposively sampled cases in Nova Scotia, Canada. Data were collected via documents and key informant interviews. Data analysis involved an in-depth analysis of each case, followed by a cross-case analysis to develop theoretically informed, generalizable knowledge on the role of scientific evidence in innovation adoption that may be applied to similar settings and contexts. RESULTS: The analyses identified key concepts alongside important caveats and considerations. Key concepts were (1) scientific evidence underpinned the adoption process, (2) evidence from multiple sources informed decision-making, (3) decision-makers considered three key issues when making decisions, and (4) champions were essential to eventual adoption. Caveats and considerations related to the presence of urgent problems and short-term financial pressures and minimizing risk. CONCLUSIONS: The findings revealed the different types of issues decision-makers consider while making these decisions and why different sources of evidence are needed in these processes. Future research should examine how different types of evidence are legitimized and why some types are prioritized over others.

Patterns of cancer centre follow-up care for survivors of breast, colorectal, gynecologic, and prostate cancer.

BACKGROUND: Rising demand on cancer system resources, alongside mounting evidence that demonstrates the safety and acceptability of primary care-led follow-up care, has resulted in some cancer centres discharging patients back to primary care after treatment. At the same time, the ways in which routine cancer follow-up care is provided across Canada continue to vary widely. The objectives of the present study were to investigate patterns of routine follow-up care at a cancer centre for breast, colorectal, gynecologic, and prostate cancer survivors; factors associated with receipt of follow-up care at a cancer centre; and changes in follow-up care at a cancer centre over time. METHODS: We identified all people diagnosed in Nova Scotia with an invasive breast, colorectal, gynecologic, or prostate cancer between 1 January 2006 and 31 December 2013. We linked the resulting population-based dataset, at the patient level, to cancer centre or clinic data and to census data. We identified a nonmetastatic survivor cohort (n = 12,267) and developed decision rules to differentiate routine from non-routine visits during the follow-up care period (commencing 1 year after diagnosis). Descriptive statistics were computed to describe the patterns of routine follow-up care at a cancer centre. Negative binomial regression was used to examine factors associated with visits made and changes over time. RESULTS: Nearly half the survivors (48.4%) had at least 1 follow-up visit to the cancer centre, with variation by disease site (range: 30.2%-62.4%). Disease site and stage at diagnosis were associated with receipt of follow-up care at a cancer centre. For instance, compared with breast cancer survivors, survivors of gynecologic cancer had more visits [incidence rate ratio (irr): 1.48; 95% confidence interval (ci): 1.34 to 1.64], and survivors of colorectal cancer had fewer visits (irr: 0.45; 95% ci: 0.40 to 0.51). Year of diagnosis was associated with follow-up at a cancer centre, with each successive calendar year being associated with an 8% increase in visits made (irr: 1.08; 95% ci: 1.07 to 1.10). CONCLUSIONS: Despite evidence that follow-up care can be effectively and safely delivered in primary care, and despite intensifying demands on oncology services, many survivors continue to receive routine follow-up care at a cancer centre.

Cross-disciplinary research in cancer: an opportunity to narrow the knowledge-practice gap.

Health services researchers have consistently identified a gap between what is identified as "best practice" and what actually happens in clinical care. Despite nearly two decades of a growing evidence-based practice movement, narrowing the knowledge-practice gap continues to be a slow, complex, and poorly understood process. Here, we contend that cross-disciplinary research is increasingly relevant and important to reducing that gap, particularly research that encompasses the notion of transdisciplinarity, wherein multiple academic disciplines and non-academic individuals and groups are integrated into the research process. The assimilation of diverse perspectives, research approaches, and types of knowledge is potentially effective in helping research teams tackle real-world patient care issues, create more practice-based evidence, and translate the results to clinical and community care settings. The goals of this paper are to present and discuss cross-disciplinary approaches to health research and to provide two examples of how engaging in such research may optimize the use of research in cancer care.

Clinical information available to oncologists in surgically treated rectal cancer: room to improve.

INTRODUCTION: In rectal cancer, decisions about the use of adjuvant and neoadjuvant treatment rely on clinical information from a variety of sources. Currently, the quality and accuracy of the aggregate of this clinical information is unclear. The objectives of the present study were to evaluate the completeness and quality of clinical information available to oncologists managing rectal cancer. METHODS: All patients diagnosed with rectal cancer in Nova Scotia between 2001 and 2005 were identified through the provincial cancer registry. The registry was linked to other administrative databases to obtain demographic, diagnostic, and treatment data. Patients undergoing radiation oncology consultation were identified, and a standardized review of the cancer centre chart was performed on a random sample, stratified by year. RESULTS: For the 222 patients reviewed, the relevant endoscopy report was present in 113 cases (51%). The level of the tumour was documented in 75% of those reports, and colonoscopy completeness, in 81%. The relevant operative report was available in 192 cases (87%). Tumour level was described in 59% of those reports, and local extension, in 73%. Elements of total mesorectal excision were partially described in 97%. In pathology reports (10% of which were synoptic), we observed significant variability in the presence of important elements. Reporting of those elements was significantly better in the synoptic pathology reports. CONCLUSIONS: Clinical information related to adjuvant and neoadjuvant therapy decision-making in rectal cancer is often not available or incomplete. A synoptic reporting system in endoscopy, surgery, and pathology could potentially be a beneficial tool in rectal cancer care.

Obesity and lifestyle risk factors for gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma.

The aim of this study was to examine the association of obesity with esophageal adenocarcinoma, and with the precursor lesions Barrett esophagus and gastroesophageal reflux disease (GERD). This case-control study included cases with GERD (n = 142), Barrett esophagus (n = 130), and esophageal adenocarcinoma (n = 57). Controls comprised 102 asymptomatic individuals. Using logistic regression methods, we compared obesity rates between cases and controls adjusting for differences in age, gender, and lifestyle risk factors. Relative to normal weight, obese individuals were at increased risk for esophageal adenocarcinoma (Odds Ratio [OR] 4.67, 95% Confidence Interval [CI] 1.27-17.9). Diets high in vitamin C were associated with a lower risk for GERD (OR 0.40, 95% CI 0.19-0.87), Barrett esophagus (OR 0.44, 95% CI 0.20-0.98), and esophageal adenocarcinoma (OR 0.21, 95% CI 0.06-0.77). For the more established risk factors, we confirmed that smoking was a significant risk factor for esophageal adenocarcinoma, and that increased liquor consumption was associated with GERD and Barrett esophagus. In light of the current obesity epidemic, esophageal adenocarcinoma incidence rates are expected to continue to increase. Successful promotion of healthy body weight and diets high in vitamin C may substantially reduce the incidence of this disease.

Evolution and critical appraisal of anastomotic technique following resection of esophageal adenocarcinoma.

The aim of this study was to critically evaluate acute and long-term complications of hand-sewn and semimechanical cervical esophagogastric anastomosis following resection of primary esophageal adenocarcinoma. Between February 1991 and 2001, 91 consecutive patients underwent subtotal esophagectomy (transthoracic, n=49; transhiatal, n=42), transposing a gastric tube based on the right gastroepiploic artery. All esophagogastric anastomoses were performed in the left neck using a hand-sewn technique (n=53) and, from September 1997, a side-to-side semimechanical technique (n=38). Outcomes evaluated were anastomotic leak rates, length of stay, and development of strictures. Postoperative mortality was 4.4% (all cardiopulmonary causes). Fifty-eight patients (63.7%) had an uncomplicated postoperative course, with a median postoperative length of stay of 10 days (vs. 20 days with associated morbidity; P

Ontogeny of humoral heart rate regulation in the embryonic mouse.

Catecholamines, acetylcholine, and adenosine are known to influence cardiac function, yet the effects of these agents on mammalian embryonic myocardium are largely unknown. To address this issue, we compared the chronotrophic effects of adenosinergic, adrenergic, and muscarinic agents on cultured murine embryos from postcoital day (PC) 8.0, when the fusing heart tubes first begin to beat, to PC 14, when cardiogenesis is essentially complete. At PC 8.0 and older, A(1)-adenosine receptor (A(1)AR) activation significantly decreased heart rates. Adrenergic stimulation caused modest increases in heart rates (145-155% of baseline) beginning at PC 9.0. Muscarinic activation decreased heart rates only after PC 13. When receptor gene expression was examined, A(1)ARs and beta(1)ARs were expressed in isolated hearts as early as PC 9.0, and beta(2)ARs and m(2)-muscarinic receptor genes were expressed at PC 11.0. These results identify the adenosinergic system as the earliest and most potent regulator of embryonic cardiac function and show that prenatal responsiveness to catecholamines and acetylcholine develops at later embryonic stages.

Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes.

INTRODUCTION: Although sentinel lymph node (SLN) status is the most powerful predictor of prognosis in patients with clinically localized melanoma, a proportion of melanoma patients with histologically negative SLNs will still recur. It is hypothesized that tumor response may be altered or mediated by specific cytokines. We therefore investigated whether levels of IL-4, IL-6, IL-10, TNF-alpha, or IFN-gamma would predict disease recurrence in melanoma patients with histologically negative SLNs. METHODS: This prospective cohort study involved 218 patients with clinically localized melanoma who underwent a histologically negative SLN biopsy. Preoperative plasma cytokine levels were determined by enzyme-linked immunosorbent assay on these patients, as well as on 90 healthy controls. Kaplan-Meier life tables were constructed, and Cox proportional hazards analyses were performed to assess predictors of disease-free survival (DFS). RESULTS: At a median follow-up of 43 months, 33 of 218 patients (15%) had suffered disease recurrence. Melanoma patients had significant elevations of IL-4, IL-6, and IL-10 compared to healthy controls; levels of IFN-gamma were less elevated in melanoma patients compared to controls. Despite this, melanoma patients with detectable IFN-gamma levels were at significantly higher risk for recurrence compared to patients with undetectable levels (5-year DFS 70% vs. 86%, P = .03). On multivariate analysis including standard melanoma prognostic factors, only tumor thickness (P = .004) and the presence of detectable IFN-gamma levels (P = .05) were significant independent prognostic factors for disease-free survival. CONCLUSIONS: Among melanoma patients with clinically localized disease who have undergone a histologically negative SLN biopsy, presence of a detectable plasma level of IFN-gamma is an independent predictor of disease recurrence. Elevated levels of IFN-gamma may identify a group of early-stage melanoma patients who are more likely to have recurrence of disease and who may benefit from adjuvant therapies, including immunotherapies.

Hepatitis B or C virus serology as a prognostic factor in patients with hepatocellular carcinoma.

It is not clear whether chronic hepatitis B or C virus (HBV or HCV) infection is a prognostic factor for hepatocellular carcinoma. We performed this study to determine if chronic HBV or HCV infection had any impact on postresection survival or affected patterns of failure. The records of 77 patients undergoing surgical resection for hepatocellular carcinoma between January 1990 and December 1998 were reviewed. Forty-four patients (57%) had HCV infection, 18 patients (23%) had HBV infection, and 15 patients (20%) had negative serology. There were no differences in age, sex, or tumor size among the groups, and all patients had margin-negative resections. There was a significantly higher incidence of satellitosis and vascular invasion in patients with HCV infection (32% and 41% respectively; P <0.05 vs. other groups). With a median follow-up of 30 months, a significantly decreased local disease-free survival (LDFS) was seen in HBV-positive (5-year LDFS 26%) or HCV-positive (5-year LDFS 38%) patients compared to those with negative serology (5-year LDFS 79%; P <0.05). There was also a trend toward a decreased overall survival in patients with positive hepatitis serology compared to patients with negative serology (37% vs. 79%; P = 0.12). Univariate analysis revealed that only satellitosis was related to local recurrence and overall survival. Patients with positive serology for hepatitis B or C undergoing resection for hepatocellular carcinoma have a trend toward worse overall prognosis and a significantly decreased LDFS when compared to patients with negative serology.

Limitations of size as a criterion in the evaluation of adrenal tumors.

BACKGROUND: Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that have been identified incidentally. However, small adrenal cortical cancers have been reported from multiple centers. METHODS: We retrospectively evaluated the value of tumor size and other clinical parameters in the prediction of the presence of adrenal malignancy. RESULTS: The records of 117 patients who underwent evaluation for tumors of the adrenal gland were reviewed. The median tumor size of the adrenal cortical carcinomas (n = 38 carcinomas) was 9.2 cm (range, 1.7-30 cm); 5 cancers (13.5%) were smaller than 5.0 cm. The median overall size of the benign tumors, excluding pheochromocytomas, was 4.0 cm (n = 38 carcinomas); 10 benign tumors (26%) were larger than 5.0 cm. The imaging features of 4 of 5 small adrenal cancers predicted malignancy; the remaining patients had hormonally functioning tumors. The imaging features of 7 of 10 large benign adrenal tumors predicted benign histologic features, including 5 of 5 myelolipomas. CONCLUSIONS: Although size remains a good predictor of the histologic features and clinical behavior of adrenal neoplasms, both small adrenal cortical cancers and large benign tumors occur with measurable frequency. High-quality imaging studies may be helpful in the identification of relatively small adrenal cancers and of characteristic benign lesions that may be selectively followed.

Long term follow up of the utility of troponin T to assess cardiac risk in stable chronic hemodialysis patients.

Thirty long-term, stable hemodialysis patients were followed 24 months to identify any predictable relationship between elevated serum cTnT values and the diagnosis of coronary artery disease and/or the occurrence of a cardiac death. Patients with a baseline cTnT value of >0.1 microg/L were at high risk for life-threatening cardiac events during the 2 years follow-up. With regard to predicting a cardiac event, cTnT has a specificity of 93.75% and sensitivity of 81.8% compared to cTnI whose specificity was 87.5% but sensitivity of between 9.1 and 18.2%. CK-MB was the most specific at 100% but had a low sensitivity of 9.1%. The hemodialysis process, while causing an increase in the serum levels of all the markers studied except CK, the increase only proved significant for cTnT. The only markers whose stratification remained consistent over the 2 years where cTnT and CK-MB, for all others a gain or lose was registered. Baseline stratification using cTnT with a cut-off value of >0.1 microg/L offers opportunities to select at risk hemodialysis patients for corrective cardiovascular intervention.

Cost and utilization impact of a clinical pathway for patients undergoing pancreaticoduodenectomy.

BACKGROUND: When implemented in several common surgical procedures, clinical pathways have been reported to reduce costs and resource utilization, while maintaining or improving patient care. However, there is little data to support their use in more complex surgery. The objective of this study was to determine the effects of clinical pathway implementation in patients undergoing elective pancreaticoduodenectomy (PD) on cost and resource utilization. METHODS: Outcome data from before and after the development of a clinical pathway were analyzed. The clinical pathway standardized the preoperative outpatient care, critical care, and postoperative floor care of patients who underwent PD. An independent department determined total costs for each patient, which included all hospital and physician costs, in a blinded review. Outcomes that were examined included perioperative mortality, postoperative morbidity, length of stay, readmissions, and postoperative clinic visits. RESULTS: From January, 1996 to December, 1998, 148 consecutive patients underwent PD or total pancreatectomy; 68 before pathway development (PrePath) and 80 after pathway implementation (PostPath). There were no significant differences in patient demographics, comorbid conditions, underlying diagnosis, or use of neoadjuvant therapy between the two groups. Mean total costs were significantly reduced in PostPath patients compared with PrePath patients ($36,627 vs. $47,515; P = .003). Similarly, mean length of hospital stay was also significantly reduced in PostPath patients (13.5 vs. 16.4 days; P = .001). The total cost differences could not be attributed solely to differences in room and board costs. Cost and length-of-stay differences remained when outliers were excluded from the analysis. Despite these findings, there were no significant differences between PrePath and PostPath patients in terms of perioperative mortality (3% vs. 1%), readmissions within 1 month of discharge (15% vs. 11%), or mean number of clinic visits within 90 days of discharge (3.3 vs. 3.4 visits). CONCLUSIONS: The establishment of a clinical pathway for PD patients dramatically reduced costs and resource utilization without any apparent detrimental effect on quality of patient care. These findings support the implementation of clinical pathways for PD patients, as well as investigation into pathway care for other complex surgical procedures.

How many lymph nodes are enough during sentinel lymphadenectomy for primary melanoma?

BACKGROUND: Sentinel lymph node (SLN) biopsy has been shown to reliably identify nodal metastases and the subsequent need for further surgical and adjuvant therapy in patients with cutaneous melanoma. Although SLN identification rates have improved with the addition of radioactive colloid to the blue dye technique, it remains unclear how many lymph nodes should be removed to accurately determine the histologic status of the nodal basin. The objective of this study was to determine the optimal extent of SLN biopsy in these patients. METHODS: The records of 633 consecutive patients with melanoma (765 nodal basins) whose primary treatment included SLN biopsy with the use of a combination of blue dye and technetium Tc 99 labeled sulfur colloid were reviewed. SLN biopsy consisted of the removal of all of the blue-stained nodes and all nodes with radiotracer uptake activity of at least twice background. RESULTS: SLN biopsy was successful in 765 of 772 basins (99%). A mean of 1.9 SLNs (median, 2 SLNs) per basin were excised. At least 3 SLNs were removed in 176 basins (23%). The overall histologic status of a basin was always established by the first or second SLN harvested (ie, in no patient was the third or subsequent SLN positive when 1 of the first 2 was not). Of the 124 basins containing lymphatic metastases, the SLN that contained the maximal radiotracer uptake (hottest) and/or stained blue was pathologically positive in 118 basins (95%). In only 6 of the 124 positive basins (5%) was the sole evidence of occult nodal metastases identified in an SLN that was neither blue-stained nor the hottest. All but 1 of these SLNs had counts that were at least 66% of the hottest node in the basin. CONCLUSIONS: With a combined modality approach to SLN biopsy, removal of more than 2 SLNs did not provide information that upstaged any patient with primary melanoma. Removal of additional nonblue SLN(s) that contained radioactive counts of at least twice background but lower than two thirds of the SLNs with maximal radiotracer uptake affected patient management in less than 0.2% of all cases. These findings may be helpful in minimizing the extent of surgery and perhaps in reducing the costs and resource use associated with operating room time and pathologic examination.

Outcomes research in surgical oncology.

BACKGROUND: There have been significant developments and advances in the area of outcomes research in the past 25 years. Unfortunately, many surgical oncologists may not have a clear concept of outcomes research and the methodology involved. METHODS: A literature-based review article was done that included an overview of outcomes research, and study design and types, outcome measures, outcome instruments, and sources of outcome data were examined. In addition, we reviewed small area variation/volume outcome analysis as well as quality-of-life studies and their applications in surgical oncology clinical investigation. Specific examples from surgical oncology were identified. RESULTS: As the costs of health care have increased, so has the emphasis on measuring outcomes of medical and surgical care to determine the quality and appropriateness of care. Marked variations in a variety of outcomes after oncological procedures have been attributed to individual surgeon and institution characteristics. Because much of the clinical surgical oncology literature deals only with the traditional mortality and morbidity outcomes, a more comprehensive examination of patient outcomes is required to fully evaluate the impact of patient management decisions. Health-related quality of life can be measured and analyzed in several ways and decisions regarding the use of such methodology are dependent on multiple factors. CONCLUSIONS: Surgical oncologists should recognize that the true value of their interventions requires systematic and comprehensive examination of patient outcomes.

Significance of multiple nodal basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy.

BACKGROUND: Although previous studies have demonstrated that truncal site is associated with an adverse prognosis, explanations for such risk are lacking. In addition, the number of nodal basins as well as the number of lymph nodes containing regional metastases are important prognostic factors in these patients. Because the lymphatic drainage pattern of truncal melanoma often includes more than one basin, we designed a study to evaluate (1) whether patients with multiple nodal basin drainage (MNBD) were at an increased risk of lymph node metastases identified by sentinel lymph node (SLN) biopsy, and (2) whether the histological status of an individual basin reliably predicted the status of the other draining basins in patients with MNBD. METHODS: The records of 295 consecutive truncal melanoma patients who were managed primarily with intraoperative lymphatic mapping and SLN biopsy, between 1991 and 1997, were reviewed. All patients underwent preoperative lymphoscintigraphy, which established the number and location of draining nodal basins. Univariate and multivariate analyses of relevant clinicopathological factors were performed to assess which factors may predict the presence of a pathologically positive SLN. RESULTS: At least one SLN was identified in 281 patients. MNBD was present in 86 (31%) patients, and a pathologically positive SLN was found in 56 (20%) patients. By multivariate analysis, the presence of MNBD (relative risk = 1.9; P = .03), tumor thickness (P = .007), and tumor ulceration (relative risk = 2.4; P = .01) were significant independent risk factors for the presence of at least one pathologically positive SLN. SLN pathology in one basin did not predict the histology of other basins in 19 (22%) of 86 patients with MNBD. CONCLUSIONS: MNBD is independently associated with an increased risk of nodal metastases in truncal melanoma patients. Because the histological status of an individual basin did not reliably predict the status of the other draining basins in patients with MNBD, it is important to adequately identify and completely assess all nodal basins at risk, as defined by lymphoscintigraphy, in truncal melanoma patients.

Using urinary biomarkers to evaluate renal effects of a Cox-2 NSAID in volunteers.

We explored urinary biomarkers as an alternative for measuring the effect of an experimental COX-2 inhibitor on renal function in volunteers. Thirty male volunteers between the ages of 20-40 were enrolled and a COX-2 NSAID was given in a blinded design. The acute administration of an oral COX-2 NSAID resulted in a consistent increase in the urinary enzyme AAP at 2 hours. At 24 hours after COX-2 NSAID administration values for most of the urinary biomarkers had returned to baseline suggesting that such effects are transient and without clinical significance in situations of acute administration.