Search

Functional overactive bladder disorder is one of the most prevalent presentations of bladder and bowel dysfunction in children, and it is associated with lower overall cardiac autonomic and parasympathetic activity. Antimuscarinics are the most frequently used pharmacological agents for treatment of children with functional overactive bladder disorder; however, there is a gap in the literature in describing the effect of antimuscarinics on the autonomic profile of this population. The aim of the study was to assess the cardiac parasympathetic activity before and after 12 weeks of oxybutynin treatment in children with overactive bladder. This was a single-institution prospective cohort study. Cardiac autonomic activity was assessed during storage and voiding phases of the bladder function via spectral analysis of heart rate variability and impedance cardiography. The primary outcome measure was high frequency, a proxy for parasympathetic nervous system activity. Parameters of uroflow study, severity of symptoms, and quality of life outcomes were also assessed. Ten children (7 females) diagnosed with overactive bladder with a median age of 10 years (range = 6–14) were followed up for a median treatment duration of 11.8 weeks (range = 6–19.4). After treatment, there was a significant reduction in high frequency during the storage phase (median change = −24.17%, p = 0.047). No change was observed in the other outcome measures except for the overall Symptom Score for Dysfunctional Elimination Syndrome after treatment (5-point decrease, p = 0.034) (Summary Table). The findings of the present follow-up study suggest that the use of oxybutynin in children with overactive bladder is associated with a significant reduction in the activity of the parasympathetic nervous system. The clinical implications of this finding are important because similar autonomic profiles (as markers of chronic stress) have been shown to be associated with increased inflammation and are found in major chronic diseases. The authors caution making a clinical connection between the heart rate variability profile of the patients in this study and patients with chronic diseases because oxybutynin is usually not administered as long-term treatment for overactive bladder. Use of oxybutynin was associated with reduction in cardiac parasympathetic activity of children with functional overactive bladder. Further investigation into the role of the autonomic nervous system as a treatment target in the management of these children is warranted. Summary Table Autonomic and uroflowmetric profile at baseline and post-treatment. Summary Table Baseline Post-treatment Relative change from baseline to post-treatment (%) P -value Autonomic variables High frequency (ms2/Hz) 672.58 (303.74–1053.63) 540.09 (283.54–671.67) −24.17 (−55.37 to −10.74) 0.047 Total power (ms2/Hz) 1159.81 (767.35–1560.37) 1106.96 (868.53–1238.00) −13.00 (−40.00 to 12.25) 0.333 Pre-ejection period (ms) 112.12 (107.42–115.35) 112.35 (105.06–121.11) 1.19 (−4.94 to 5.61) 0.767 Heart rate (beats/min) 78.61 (74.89–83.65) 84.44 (73.09–87.18) 5.31 (−0.50 to 9.23) 0.139 Uroflowmetric variables Peak urinary flow rate (ml/s) 11.4 (5.2–22.2) 10.8 (5.6–15.1) −36.1 (−57.2 to 183.9) 0.508 Calculated peak urinary flow index [15] 0.7 (0.3–1.0) 0.6 (0.4–0.9) −17.3 (−52.0 to 160.7) 0.646 Average urinary flow rate (ml/s) 4.4 (2.2–9.8) 2.5 (1.2–5.0) −41.2 (−82.7 to 87.8) 0.139 Calculated average urinary flow index [15] 0.6 (0.4–1.2) 0.4 (0.1–0.7) −50.0 (−76.2 to 27.9) 0.241 Voided volume (ml) 82.5 (27.6–128.6) 45.6 (25.3–92.4) −58.2 (−71.3 to 199.2) 0.646 Postvoid residual (mL) 0 (0–13.8) 10.0 (0–66.3) – 0.345 Calculated ratio of actual to expected bladder capacity [15] 0.23 (0.18–0.46) 0.34 (0.14–0.74) −8.3 (−69.9 to 270.6) 0.374 Uroflow curve, n abnormal (%) 5/9 (56) 8/8 (100) – N/A BBD score 23 (19–31) 18 (14–22) – 0.034 PinQ score 37 (26–49) 35 (13–48) – 0.206 Values are medians (interquartile range). P -values are reported using the Wilcoxon signed-rank test. BBD = bladder and bowel dysfunction, N/A = not applicable, PinQ = Pediatric Incontinence Quality-of-Life questionnaire. [ABSTRACT FROM AUTHOR]

To evaluate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) using aggregate-level data from resectable esophageal or gastroesophageal junction cancer (EC/GEJC) trials assessing therapies in (neo)adjuvant and perioperative settings. A systematic literature review was conducted to identify trials reporting OS and DFS, or compatible progression-free survival (PFS). Bivariate random-effects meta-analysis was used to estimate correlation between the treatment effects on DFS/PFS and OS, and weighted linear regression models assuming trial sample sizes as weights were used to estimate surrogacy equations. The primary analysis consisted of trials across all treatment settings, and secondary analysis consisted of trials only in the adjuvant setting. Leave-one-out cross-validation (LOOCV) was performed to measure the stability and predictive accuracy of the surrogacy equations while surrogate threshold effects (STE)—the minimum treatment effect on DFS/PFS that would translate into a positive OS benefit—were derived to measure their usefulness. The primary analysis included 26 trials. The estimated correlation coefficient between the hazard ratio (HR) of DFS/PFS (HR DFS/PFS) and HR of OS (HR OS) was 0.83 (95% confidence interval [CI]: 0.70–0.90). The estimated surrogacy equation was log(HR OS) = 0.80 × log(HR DFS/PFS) with a corresponding STE of 0.82. Reported HR OS was within the 95% prediction interval of the predicted HR OS from the model for more than 95% of the trials in the LOOCV, indicating a valid model. Secondary analysis included 7 trials with an estimated correlation coefficient of 0.76 (95% CI: 0.18–0.95). Through LOOCV, the surrogacy equation in the adjuvant setting was deemed valid. Our meta-analysis suggests that HR DFS/PFS —where DFS/PFS is defined as time from resection to disease recurrence (local, locoregional, or distant) or death—is correlated to HR OS , and a valid and useful surrogate predictor for HR OS in the neoadjuvant, perioperative, or adjuvant settings. • First published DFS/OS surrogacy analysis spanning all treatment settings in EC/GEJ. • Meta-analysis of 26 trials suggests correlated hazard ratios for DFS and OS. • DFS can be a valid and useful surrogate for OS in resectable EC/GEJ. [ABSTRACT FROM AUTHOR]