A Structured Training for Trans Anal Irrigation in Pediatric Patients Improves Outcomes and Reduce Failures: Results of an Interventional Multicenter Prospective Study.

BACKGROUND: Continence issues due to organic causes including previous colorectal surgery or neurological issues might benefit from Transanal irrigation (TAI) that proved to be highly effective but with a number of limitations including a relatively high discontinuation rates. Our study was aimed at evaluating the efficacy of an advanced protocol tailored to each patient to prevent dropout and increase satisfaction, independence, and quality of life. MATERIALS AND METHODS: This was a prospective, interventional, multicenter, nonrandomized study involving children aged 4-18 years with bowel dysfunction unresponsive to conventional treatments who required TAI. TAI was performed in accordance to the best standards of care with a total irrigation volume that was determined based on low emission X-Ray barium enemas performed at the very beginning of the study. All patients underwent training and assessments of continence, patients' perspectives and quality of life were performed at different timepoints from enrollment (T0) up to 6 months since TAI was introduced (T3). RESULTS: A total of 78 patients were enrolled. Male to female ratio was 1.4:1. Mean age at enrollment was 106.1 ± 42.8 months. Discontinuation was reported by 3 patients (3.8 %). Continence, satisfaction and a number of other outcome measures increased from baseline (T0) to the last visit (T3). In particular, mean Rintala total score increased linearly from 7.8 to 14.8 during the study period (T0 to T3 timepoints). On a multivariate analysis, the only parameter that proved to be inversely associated with continence as well as with other outcome measures was the use of laxatives at enrollment and during the study. CONCLUSIONS: This study has demonstrated the high efficacy of this innovative patient-tailored TAI protocol across all assessed scores. Of note, given the negative impact of laxatives, our findings suggest limiting their use in this patient population to further increase the efficacy of the procedure.

Intramedullary epidermoid cyst presenting with abnormal urological manifestations.

STUDY DESIGN: Report of an epidermoid cyst with intramedullary localization. OBJECTIVE: To describe an atypical presentation of intramedullary epidermoid cyst. SUMMARY OF BACKGROUND DATA: Intramedullary epidermoid cysts are rare entities with a marked variability in the clinical presentation, essentially of neurological pertinence. METHODS: Case report of a spinal epidermoid cyst in a 13-year-old girl presenting with urological symptoms: she had a 12-month history of recurrent low urinary tract infections, urinary frequency and nocturnal enuresis. A urodynamic evaluation was performed and showed the presence of involuntary bladder contractions with detrusor instability and low bladder compliance. Magnetic resonance imaging of the spine demonstrated an intramedullary lesion of the dorsal spinal cord. RESULTS: The mass was excised and 6 months after surgical excision, urological manifestations improved with decreased detrusor hyper-reflexia, increased bladder capacity and compliance and no later report of urinary tract infections. CONCLUSIONS: In our patient, unusual clinical manifestations of the tumor have delayed the diagnosis, but its complete removal has led to remission of symptoms. Detailed neurological examination and investigations are indicated in patients with clinical and urodynamic features, suggestive of neuropathic bladder.

Quantitative analysis of ES-285, an investigational marine anticancer drug, in human, mouse, rat, and dog plasma using coupled liquid chromatography and tandem mass spectrometry.

A method was developed for the quantitative analysis of the novel anticancer agent ES-285 (spisulosine; free base) in human, mouse, rat, and dog plasma using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry in order to support pre-clinical and clinical studies with the drug. Sample preparation was carried out by protein precipitation with acetonitrile, containing isotopically labeled (d(3)) ES-285 as internal standard. Aliquots of 10 micro l of the supernatant were injected directly on to an Inertsil ODS-3 column (50 x 2.0 mm i.d., 5 micro m). Elution was carried out using methanol-10 mM ammonium formate (pH 4) in water (80 : 20, v/v) pumped at a flow-rate of 0.2 ml min(-1) with a run time of 8 min. Multiple reaction monitoring chromatograms obtained on an API365 triple-quadrupole mass spectrometer were used for quantification. The lower limit of quantitation (LLOQ) was 10 ng ml(-1) in human, mouse, rat, and dog plasma and the linear dynamic range extended to 500 ng ml(-1). A full validation of the method was performed in human plasma, and partial validations were performed in mouse, rat and dog plasma. Accuracies and precisions were <20% at the LLOQ concentration and <15% for all other concentrations in all matrices. ES-285 was stable during all steps of the assay. Thus far this method has been used successfully to analyze over 500 samples in pre-clinical trials, and will be implemented in the planned clinical phase I studies.

Carcinoid tumors of the appendix in children: two case reports and review of the literature.

Carcinoid is the most common tumor of the appendix. Reported incidence in pediatric population is 1 per 100,000 per annum. Clinical presentation like acute appendicitis is frequent, but carcinoid tumor can be an incidental finding during surgical procedures other than appendectomy. Size and depth of invasion are important prognostic criteria and tumors larger than 2 cm metastasize more frequently than smaller ones. Simple appendectomy is considered appropriate treatment, while right colectomy is indicated in tumor bigger than 2 cm. The authors report 2 cases of carcinoid tumors of the appendix in children, smaller than 2 cm treated with appendectomy alone, and disease free at follow-up.

Side-effects of oral or intravesical oxybutynin chloride in children with spina bifida.

OBJECTIVE: To evaluate the incidence of side-effects of oral and intravesical oxybutynin chloride in children with meningomyelocele (MMC) and a neurogenic bladder. PATIENTS AND METHODS: The study comprised 225 children with a neurogenic bladder from MMC who were evaluated with urodynamic testing and voiding cysto-urethrography to identify those at high risk of upper tract damage. In all, 101 children (mean age 4.2 years, range 0.25-10) had unco-ordinated detrusor-sphincter function and low compliance; they were treated with either oral or intravesical oxybutynin and clean intermittent catheterization. RESULTS: Of the 101 patients, 67 were treated with oral oxybutynin; in 11 the treatment was discontinued because of the side-effects. The other 34 patients used both clean intermittent catheterization and intravesical oxybutynin. In this group there were side-effects in six patients, including drowsiness, hallucinations and cognitive changes. CONCLUSIONS: Oral and intravesical oxybutynin is effective for managing neurogenic bladder dysfunction, but intravesical administration is safer and better tolerated than oral oxybutynin in the treatment of children with MMC. However, adverse effects such as cognitive impairment can also occur in children treated with intravesical oxybutynin and these patients must be closely monitored because these effects may differ from those with oral administration.

Immunohistochemical and pharmacokinetic characterization of site-specific immunoconjugate 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine derived from anti-breast carcinoma monoclonal antibody 15A8.

In this study, the breast carcinoma-reactive monoclonal antibody 15A8 and a site-specific immunoconjugate of the antibody, 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine (15A8-GYK-DTPA), were characterized by immunohistological methods for reactivity with normal and neoplastic human tissues and normal cynomolgus monkey tissues. In addition, 15A8-GYK-DTPA labeled with 111In was assessed by in vivo imaging and pharmacokinetic studies for localization to human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar limited reactivity with normal human tissues. Specifically, epithelial structures, including normal breast epithelium, lung alveoli, bronchial epithelium and glands, liver bile ducts, pancreatic ducts, kidney distal and collecting tubules, epidermal and esophageal epithelium, endometrial glands, and thymic Hassall's corpuscles, were reactive. Normal monkey tissues stained with 15A8 exhibited a similar pattern of reactivities. Antibody 15A8 reacted broadly with epithelium-derived tumors; more than 60% of the cells in all of the breast, colon, non-small cell lung, ovarian, prostate, bladder, and renal carcinomas tested expressed the antigen. In contrast, a variety of nonepithelial neoplasms, including lymphomas, melanomas, sarcomas, and small cell lung carcinomas, were nonreactive. 15A8-GYK-DTPA-111In administered i.v. rapidly localized to and imaged both MX-1 and MCF-7 human breast carcinoma xenografts in nude mice, reaching maximal levels of about 20% of injected dose/g of tumor within 4 days. No unusual localization to any nontumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that seen in the blood. Furthermore, the immunoconjugate did not accumulate in xenografts of the antigen-negative breast carcinoma ZR-75-1, which indicates that tumor localization was antigen specific. Pharmacokinetic studies in cynomolgus monkeys suggested that significant amounts of 15A8-GYK-DTPA-111In did not localize to normal epithelia and demonstrated that the immunoconjugate was not toxic. These findings suggest that antibody 15A8 may be useful in the diagnosis and therapy of breast cancer and possibly other carcinomas.

Carbohydrate-derivatized immunoconjugate of the anti-(carcinoembryonic antigen) monoclonal antibody C46: immunohistological reactivity and pharmacokinetic comparison with a randomly derivatized C46 immunoconjugate.

In this study, a site-specific glycyl-tyrosyl-(N-epsilon-diethylenetriaminepentaacetic acid)-lysine (GYK-DTPA) immunoconjugate of the anti-carcinoembryonic antigen monoclonal antibody C46 (C46-GYK-DTPA) was characterized by immunohistological and immunofluorescence methods for reactivity with normal and neoplastic human tissues. In addition, pharmacokinetic studies assessed the ability of C46-GYK-DTPA labeled with 111In to localize to and image human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar patterns of reactivity with normal human tissues. C46 did not bind to the surface of normal human granulocytes, which indicates lack of reactivity with normal cross-reacting antigen. C46-GYK-DTPA reacted with 100% of the colon, breast and renal carcinomas examined and with two of three lung carcinomas, but did not react with any sarcomas, melanomas or lymphomas examined. Intravenously administered C46-GYK-DTPA-111In rapidly localized to and imaged LS174T human colon adenocarcinoma xenografts in nude mice, reaching maximal levels of about 25% of injected dose/g tumor within 1 day. No unusual localization to any non-tumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that in the blood. The accessible binding sites in 1 g tumors appeared to be saturated at an antibody dose between 100 micrograms and 1000 micrograms/mouse. Further, in a direct in vivo comparison, the site-specific conjugate C46-GYK-DTPA had more favorable pharmacokinetics and better tumor localization than a randomly derivatized C46 immunoconjugate (C46-DTPA). These findings suggest that the site-specific immunoconjugate C46-GYK-DTPA may be useful in the diagnosis and therapy of colon cancer and other adenocarcinomas expressing carcinoembryonic antigen.

A composite model for multiple assays of skin irritation.

A model for skin irritation was developed for simultaneous evaluation of the influence on irritation of abrasion, occlusion, and duration of treatment and for fulfillment of requirements for labeling considerations under DOT, CPSC-FHSA, OSHA, and EEC. This model greatly reduces the number of animals required to address submissions under multiple agencies compared to performing each test separately. In this model, which we have called a Composite Skin Irritation test, a test material is placed on three pairs of intact and abraded sites on each rabbit; one pair of sites is occluded for 4 hours, one for 24 hours, and the other left unoccluded for 24 hours. Results are presented from 88 composite tests with 80 petroleum-related materials. For the materials tested, abrasion of the skin had no effect on the irritation response. Occlusion of the test site generally did not result in dramatic increases in response, except for petroleum refinery streams with a boiling range below 500 degrees F. Exposure for 4 hours rather than 24 hours generally resulted in less irritation; however, for individual compounds, the irritation from the 4-hour exposure could not be predicted from the response to the 24-hour exposure. Of the 80 materials tested, 12 would be labeled as skin irritants under CPSC guidelines, three under OSHA, and 20 under EEC. Of the 20 that would be labeled under EEC criteria, only seven would be labeled under CPSC criteria. At least for petroleum-related materials, results from skin irritation studies performed under one set of conditions cannot be used to predict the degree of irritation that would be produced under a different set of exposure conditions.

The absence of teratogenic hazard potential of p-phenylenediamine in Sprague-Dawley rats.

Para-phenylenediamine (PPD) was administered by gavage to pregnant Sprague-Dawley Rats at dose levels of 5, 10, 15, 20, and 30 mg/kg/day on days 6 through 15 of gestation (day 0 = day sperm was found in the vagina). A sham control group and a pair fed control group were studied at the same time. Pregnant animals were killed on day 20 of gestation and 1/3 of the fetuses were examined for visceral malformations and 2/3 for skeletal malformations and variations. Significant reductions in food consumption and weight gain were noted in the 30 mg/kg and pair fed control groups. Two pregnant rats given PPD at 30 mg/kg/day died but there were no deaths in any other dose groups. Fetal evaluations showed no biologically or statistically significant increase in malformations or developmental variations in any group. Therefore, although maternal toxicity was demonstrated at the two highest dose levels, there was no evidence of teratogenic or other embryotoxic effects.