The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer

Purpose: The goal of this project was to see if using IMRT to deliver elective pelvic nodal irradiation (EPNI) for prostate cancer reduced acute treatment toxicity.

Methods: Two hundred and thirty patients were enrolled into prospective trials delivering EPNI with a concomitant hypofractionated IMRT boost to the prostate. During accrual, the method of EPNI delivery changed as new literature emerged. Three methods were used (1) 4FB, (2) IMRT with 2 cm CTV margins around the pelvic vessels as suggested by Shih et al. (2005) [7] (IMRT-Shih), and (3) IMRT with nodal volumes suggested by the RTOG (IMRT-RTOG). Initially patients were treated with an empty bladder, with the remainder treated with bladder full.

Results: Patients in the 4FB group had higher rates of grade 2 acute GI toxicities compared to the IMRT-Shih and IMRT-RTOG groups (31.9% vs 20.8% vs 7.2%, p = 0.0009). Patients in the 4FB group had higher rates of grade 3 urinary frequency compared to the two IMRT groups (8.5% vs 0% vs 0%, p = 0.027). However, multivariate analysis suggested the factor that most influenced toxicity was bladder filling followed by IMRT.

Conclusions: Bladder filling appeared to be the dominant factor which predicted for acute toxicity, followed by the use of IMRT.

Combination of CFD and DOE to analyze and improve the mass flow rate in urinary catheters

The urinary catheter is a thin plastic tube that has been designed to empty the bladder artificially, effortlessly, and with minimum discomfort. The current CH14 male catheter design was examined with a view to optimizing the mass flow rate. The literature imposed constraints to the analysis of the urinary catheter to ensure that a compromise between optimal flow, patient comfort, and everyday practicality from manufacture to use was achieved in the new design. As a result a total of six design characteristics were examined. The input variables in question were the length and width of eyelets 1 and 2 (four variables), the distance between the eyelets, and the angle of rotation between the eyelets. Due to the high number of possible input combinations a structured approach to the analysis of data was necessary. A combination of computational fluid dynamics (CFD) and design of experiments (DOE) has been used to evaluate the "optimal configuration." The use of CFD couple with DOE is a novel concept, which harnesses the computational power of CFD in the most efficient manner for prediction of the mass flow rate in the catheter. Copyright © 2009 by ASME.

Bladder continence management in adult acquired brain injury

Purpose: Persistence of urinary incontinence post acquired brain injury (ABI) carries important prognostic significance. We undertook to document the incidence of urinary incontinence, its management and complications in rehabilitation inpatients following ABI and to assess adherence to post ABI bladder management guidelines. 

Method: A retrospective chart survey of a convenience sample of consecutive admissions to two adult neurorehabilitation units Forster Green Hospital, Belfast, and the Scottish Brain Injury Rehabilitation Service, Edinburgh (SBIRSE). Bladder continence and management on transfer to and discharge from rehabilitation, trial removal of catheter, use of bladder drill, ultrasound investigation, anticholinergic medication and complications were recorded. 

Results: One hundred and forty six patients were identified. Seventy-seven (52.7%) were independent and continent of urine at rehabilitation admission and 109 (74.7%) on discharge. In all, 13 patients had urinary tract infection, 7 had urethral stricture and 1 developed haematuria whilst catheterised. Ultrasound of renal tracts was underused. Trial removal of catheter after transfer to rehabilitation occurred at a median of 10 days. 

Conclusions: Urinary continence was achieved in almost half of incontinent ABI patients during rehabilitation. There is potential for increased use of investigation of the renal tracts. Rehabilitation physicians should consider urethral stricture in the management of continence post ABI. 

Implications for Rehabilitation:

- Persisting urinary incontinence post ABI is associated with increased morbidity.

- Urethral stricture is an under-recognised complication after ABI and should be considered as a potential cause of incontinence in this patient group.

- Gains in urinary continence are seen in patients post ABI, managed with various interventions.

- Goal setting offers an opportunity to focus on bladder management rather than simply continence and may allow improvement in rate of appropriate investigation

Cadaveric fascia lata pubovaginal slings:early results on safety, efficacy and patient satisfaction

Objective To prospectively evaluate and quantify the efficacy of cadaveric fascia lata (CFL) as an allograft material in pubovaginal sling placement to treat stress urinary incontinence (SUI).

Patients and methods Thirty-one women with SUI (25 type II and six type III; mean age 63 years, range 40-75) had a CFL pubovaginal sling placed transvaginally. The operative time, blood loss, surgical complications and mean hospital stay were all documented. Before and at 4 months and 1 year after surgery each patient completed a 3-day voiding diary and validated voiding questionnaires (functional inquiry into voiding habits, Urogenital Distress Inventory and Incontinence Impact Questionnaire, including visual analogue scales).

Results The mean (range) operative time was 71 (50-120) min, blood loss 78.7 (20-250) mL and hospital stay 1.2 (1-2) days; there were no surgical complications. Over the mean follow-up of 13.5 months, complete resolution of SUI was reported by 29 (93%) patients. Overactive bladder symptoms were present in 23 (74%) patients before surgery, 21 (68%) at 4 months and two (6%) at 1 year; 80% of patients with low (<15 cmH (2) O) voiding pressures before surgery required self-catheterization afterward, as did 36% at 4 months, but only one (3%) at 1 year. Twenty-four (77%) patients needed to adopt specific postures to facilitate voiding. After surgery there was a significant reduction in daytime frequency, leakage episodes and pad use (P <0.05). The severity of leak and storage symptoms was also significantly less (P <0.002), whilst the severity of obstructive symptoms remained unchanged. Mean subjective levels of improvement were 69% at 4 months and 85% at 1 year, with corresponding objective satisfaction levels of 61% and 69%, respectively. At 1 year, approximate to 80% of the patients said they would undergo the procedure again and/or recommend it to a friend.

Conclusion Placing a pubovaginal sling of CFL allograft is a highly effective, safe surgical approach for resolving SUI, with a short operative time and rapid recovery. Storage symptoms are significantly improved, and subjective improvement and satisfaction rates are high.

Urinary thrombomodulin levels were significantly higher following occupational exposure to chemicals, in the presence of dipstick protein, but not in the presence of dipstick blood

Currently, there are no biomarkers which can identify patients with an increased risk of developing urothelial cancer as a result of occupational chemical exposure. The aim of this study was to evaluate the relationships between final diagnosis and 22 biomarkers measured in urine, serum and plasma collected from 156 hematuric patients. Fourteen of the 80 patients (17.5%) with urothelial cancer and 13/76 (17.1%) of the controls were deemed to have a history of chemical exposure. We applied Fisher's exact tests to explore associations between chemical exposure and final diagnosis, and tumor stage and grade, where applicable; ANOVA and t-test to compare age across patients with and without chemical exposure; and Zelen's exact test to evaluate relationships across final diagnosis, chemical exposure and smoking. Following pre-selection of biomarkers using Lasso, we identified biomarkers with differential levels across patients with and without chemical exposure using Welch's t-test. Using a one-sided t-test and considering multiple testing using FDR, we observed that TM levels in urine were significantly higher in samples from patients with a history of chemical exposure regardless of their diagnosis as control or urothelial cancer (one-sided t-test, p_UC = 0.014 and p_CTL = 0.043); in the presence of dipstick protein and when urinary pH levels ≤ 6 (p = 0.003), but not in the presence of dipstick blood (p = 0.115). Urothelial cancer patients with a history of chemical exposure were significantly younger (64.1 years) than those without chemical exposure (70.2 years) (one-sided t-test p-value = 0.012); and their tumors were higher grade (Fisher's exact test; p = 0.008). There was a strong association between a history of chemical exposure and smoking in urothelial cancer patients (Zelen's exact test; p = 0.025). Elevated urinary thrombomodulin levels could have the potential to identify chemical exposure in hematuric patients at high risk of developing urothelial cancer.

Bacteriophage Can Prevent Encrustation and Blockage of Urinary Catheters by Proteus mirabilis.

Proteus mirabilis forms dense crystalline biofilms on catheter surfaces that occlude urine flow, leading to serious clinical complications in long-term catheterized patients, but there are presently no truly effective approaches to control catheter blockage by this organism. This study evaluated the potential for bacteriophage therapy to control P. mirabilis infection and prevent catheter blockage. Representative in vitro models of the catheterized urinary tract, simulating a complete closed drainage system as used in clinical practice, were employed to evaluate the performance of phage therapy in preventing blockage. Models mimicking either an established infection or early colonization of the catheterized urinary tract were treated with a single dose of a 3-phage cocktail, and the impact on time taken for catheters to block, as well as levels of crystalline biofilm formation, was measured. In models of established infection, phage treatment significantly increased time taken for catheters to block (∼ 3-fold) compared to untreated controls. However, in models simulating early-stage infection, phage treatment eradicated P. mirabilis and prevented blockage entirely. Analysis of catheters from models of established infection 10 h after phage application demonstrated that phage significantly reduced crystalline biofilm formation but did not significantly reduce the level of planktonic cells in the residual bladder urine. Taken together, these results show that bacteriophage constitute a promising strategy for the prevention of catheter blockage but that methods to deliver phage in sufficient numbers and within a key therapeutic window (early infection) will also be important to the successful application of phage to this problem.

Quantification of urinary excretion of ethosuximide enantiomers and their major metabolites in the rat.

A chiral gas chromatographic assay has been developed for quantitative analysis of ethosuximide and its major metabolites in rat urine. The extraction procedure was found to be precise and reproducible. Recovery was in the range of 94-98%, intraday CV(%) was 0.92% for (S)-ethosuximide (50 mug/ml) and 0.51% for (R)-ethosuximide (50 mug/ml). Interday CV(%) was 1.12% for (S)-ethosuximide and 0.72% for (R)-ethosuximide. The limit of detection was determined to be around 0.01 mug/ml for each enantiomer. Following administration of rac-ethosuximide by i.v., i.p. and oral routes, unchanged ethosuximide was detected in urine up to 72h after drug administration. The appearance of all detected metabolites occurred Within 24h of drug administration. Significantly more (S)-ethosuximide was excreted unchanged than (R)-ethosuximide with all three routes studied. A substantial amount of the drug was eliminated as the 2-(1-hydroxyethyl)-2-methylsuccinimide (2 pairs of diastereoisomers). Much less drug was eliminated as the 2-ethyl-3-hydroxy-2-methylsuccinimide with only one diastereoisomer observed. Examination of the one pair of diastereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide that was resolved showed preferential excretion of one isomer. Comparison of both pairs of diastereoisomers showed that one pair was formed in preference to the other with a ratio of approximately 0.8:1. It is concluded that stereoselective metabolism of ethosuximide occurs. Copyright (C) 2001 John Wiley & Sons, Ltd. Author Keywords: chiral pharmacokinetics; ethosuximide enantiomers; metabolism; rat; urinary excretion; gas chromatography

A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type ll diabetes

The main hallmark of diabetic nephropathy is elevation in urinary albumin excretion. We performed a genome-wide linkage scan in 63 extended families with multiple members with type II diabetes. Urinary albumin excretion, measured as the albumin-to-creatinine ratio (ACR), was determined in 426 diabetic and 431 nondiabetic relatives who were genotyped for 383 markers. The data were analyzed using variance components linkage analysis. Heritability (h2) of ACR was significant in diabetic (h2=0.23, P=0.0007), and nondiabetic (h2=0.39, P=0.0001) relatives. There was no significant difference in genetic variance of ACR between diabetic and nondiabetic relatives (P=0.16), and the genetic correlation (rG=0.64) for ACR between these two groups was not different from 1 (P=0.12). These results suggested that similar genes contribute to variation in ACR in diabetic and nondiabetic relatives. This hypothesis was supported further by the linkage results.

Characterization and optimization of experimental variables within a reproducible bladder encrustation model and in vitro evaluation of the efficacy of urease inhibitors for the prevention of medical device-related encrustation

This study presents a reproducible, cost-effective in vitro encrustation model and, furthermore, describes the effects of components of the artificial urine and the presence of agents that modify the action of urease on encrustation on commercially available ureteral stents. The encrustation model involved the use of small-volume reactors (700 mL) containing artificial urine and employing an orbital incubator (at 37 degrees C) to ensure controlled stirring. The artificial urine contained sources of calcium and magnesium (both as chlorides), albumin and urease. Alteration of the ratio (% w/w) of calcium salt to magnesium salt affected the mass of encrustation, with the greatest encrustation noted whenever magnesium was excluded from the artificial urine. Increasing the concentration of albumin, designed to mimic the presence of protein in urine, significantly decreased the mass of both calcium and magnesium encrustation until a plateau was observed. Finally, exclusion of urease from the artificial urine significantly reduced encrustation due to the indirect effects of this enzyme on pH. Inclusion of the urease inhibitor, acetohydroxamic acid, or urease substrates (methylurea or ethylurea) into the artificial medium markedly reduced encrustation on ureteral stents. In conclusion, this study has described the design of a reproducible, cost-effective in vitro encrustation model. Encrustation was markedly reduced on biomaterials by the inclusion of agents that modify the action of urease. These agents may, therefore, offer a novel clinical approach to the control of encrustation on urological medical devices. (c) 2005 Wiley Periodicals, Inc.