BRAF mutation status in primary and metastatic melanomas in two regions with differing potential ultraviolet radiation exposure.

BACKGROUND: Melanoma is seen as a heterogeneous molecular entity, with solar ultraviolet radiation (UVR) and BRAF mutation status being important determinants. AIM: To study primary and metastatic melanomas from two UVR-distinct regions to elucidate correlations between prognostic predictors, UVR and BRAF mutation status. METHODS: Extended BRAF testing for 9 mutations was obtained for 95 primary melanomas [Lebanon (LB) n = 55, Pakistan (PK) n = 40)] and 65 metastatic melanomas (LB n = 36, PK n = 29). Collected data included patient age and sex, melanoma size and anatomical location, prognostic parameters and solar elastosis grade for primary melanomas. For metastatic melanomas, site of metastasis, magnitude of necrosis and degree of pigmentation were assessed. Cumulative 21-year averages of potential UVR exposure for Lebanon (110 kJ/m(2) /year) and Pakistan (128 kJ/m(2) /year) were derived from the National Center for Atmospheric Research databases. RESULTS: BRAF mutation status was obtained for 146/160 cases (91.3%). Overall mutation rate was 24/88 (27.3%) in primary and 25/58 (43.1%) in metastatic melanoma. V600E was the predominant mutation in 21/24 (87.5%) of primary and 23/25 (92%) of metastatic melanomas. A 60% discordant mutation rate was identified; of three patients, two lost the mutation in the metastasis and one gained it. The relative incidence of BRAF mutation with potential UVR exposure showed a similar trend in primary (low vs. high UVR: 32.1% vs. 20.0%) and metastatic (57.1% vs. 21.7%) melanomas (P < 0.05). Predictors of BRAF mutations were trunk location and epithelioid and mixed cytology for primary and subcutaneous metastasis, low UVR exposure and absence of pigmentation for metastatic melanomas (P < 0.05). BRAF-positive status in primary melanomas was predicted by multivariate binary logistic regression with reasonable accuracy (C-statistic = 0.67, 95% CI 0.530-0.81 with one independent predictor, namely, epithelioid cytology (OR = 5.11, 95% CI 1.38-8.88, P = 0.01). In metastatic melanomas, high UVR (OR = 0.21, 95% CI 0.06-0.07; P < 0.01) was an independent negative predictor of BRAF mutation. CONCLUSIONS: We have documented the rate of different BRAF mutation types in a Lebanese and Pakistani cohort, and assessed correlations with prognostic markers and potential UVR exposure.

Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome-associated lymphoproliferation.

OBJECTIVE: Primary Sjögren's syndrome (SS) is an autoimmune disease associated with a high risk of developing non-Hodgkin's lymphoma. This study was undertaken to determine the nature of B cells driving lymphoproliferation in primary SS. METHODS: B cell subsets and function were analyzed in peripheral blood from 66 adult patients with primary SS (including 14 patients with B cell lymphoproliferative disease [LPD]) and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. The reactivity of recombinant antibodies isolated from single B cells from patients with primary SS and LPD was tested using an enzyme-linked immunosorbent assay. RESULTS: We observed an expansion of an unusual CD21-/low B cell population that correlated with lymphoproliferation in patients with primary SS. A majority of CD21-/low B cells from patients with primary SS expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment, since their Ig genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21-/low B cells from patients with primary SS remained responsive to Toll-like receptor (TLR) stimulation. Molecules specifically expressed in CD21-/low B cells that are likely to induce their unresponsive stage were detected in gene array analyses. CONCLUSION: Patients with primary SS who display high frequencies of autoreactive and unresponsive CD21-/low B cells are susceptible to developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.

In utero intervention in a patient with prune-belly syndrome and severe urethral hypoplasia.

Prenatal ultrasound scanning of a 20-year-old woman at 17 weeks of gestation revealed findings suggestive of bladder outlet obstruction, including bladder distension, dilated bilateral ureters, urinary ascites, and oligohydramnios. Vesicoamniotic shunts were placed with decompression of the bladder and correction of the amniotic fluid levels. Labor was induced at 36 weeks' gestation. At birth, the infant was noted to have prune-belly syndrome with severe urethral hypoplasia, a variant usually associated with a poor prognosis, necessitating vesicostomy for bladder drainage. We present a case of a patient with prune-belly syndrome and bladder outlet obstruction in whom early intervention resulted in an excellent outcome with preservation of renal and pulmonary function.

Submucosal bladder neck injection of bovine dermal collagen for stress urinary incontinence in the pediatric population.

PURPOSE: The surgical management of stress urinary incontinence in the pediatric population includes various surgical techniques of which the simplest is outpatient transurethral or periurethral injection of a bulking agent. Currently purified bovine dermal collagen cross-linked with glutaraldehyde (Contigen) is the only Food and Drug Administration approved bulking agent available. Patients with stable detrusor function are ideal candidates. We review our initial experience with children. MATERIALS AND METHODS: Between January 1994 and June 1995, 23 boys and 9 girls 4 to 17 years old (mean age 9) consecutively underwent submucosal bladder neck injection with cross-linked bovine dermal collagen. Incontinence was secondary to spinal dysraphism in 24 patients, complete epispadias in 4, classic bladder exstrophy in 3 and neurogenic bladder secondary to a sacral teratoma in 1. Preoperative video urodynamics documented intrinsic sphincteric deficiency in all patients with leak point pressure of 15 to 60 cm. water (mean 37). Injection volumes ranged from 2.5 to 17 cc (mean 10). Continence results were defined as dry-requiring no protection while on a 4-hour clean intermittent catheterization program, good-improved but requiring 1 to 5 pads daily and failure-no postoperative improvement or still requiring diapers. RESULTS: Of the children with neurogenic bladder 20% became dry following the first injection and an additional 28% had a good result. Furthermore, of the 6 children with exstrophy or epispadias who underwent a Young-Dees-Leadbetter procedure 50% were dry and 17% had a good result after the first injection. Complications were limited to a febrile urinary tract infection associated with urinary retention in 1 patient and transiently worse continence in 2. CONCLUSIONS: Despite the limited success rate, we believe that transurethral collagen injection therapy has a viable role in the treatment of intrinsic sphincteric deficiency in select pediatric patients, particularly since the procedure has low morbidity and can be performed on an outpatient basis. Preoperative counseling should be given with realistic expectations.

Outcome of sling cystourethropexy in the pediatric population: a critical review.

PURPOSE: We performed a critical retrospective analysis of the records of all consecutive children who underwent sling cystourethropexy at our institutions. We particularly assessed the incidence and outcome in children who underwent enterocystoplasty in addition to a sling procedure. MATERIALS AND METHODS: Between May 1992 and August 1994, 24 girls and 15 boys 4 to 17 years old (mean age 9) consecutively underwent 1 of 4 techniques of sling cystourethropexy for stress urinary incontinence using rectus fascia via an abdominal approach. Diagnoses included spinal dysraphism in 34 patients, spinal trauma in 2, cecoureterocele in 1, epispadias in 1 and classic bladder exstrophy in 1. All children underwent preoperative video urodynamics. In 4 patients only a sling procedure was performed (group 1), while in 9 others a sling procedure was performed after enterocystoplasty (group 2). In 26 patients a sling procedure and concomitant enterocystoplasty were performed (group 3). RESULTS: Patients who underwent concomitant enterocystoplasty had more hyperactive preoperative urodynamics than those who did not. Postoperative continence was subcategorized in terms of patient age, sex, diagnosis (neurogenic versus nonneurogenic), preoperative video-urodynamics, surgeon technique, group (that is with or without cystoplasty) and type of enterocystoplasty (that is stomach versus ileum). Of these factors only concomitant enterocystoplasty was predictive of postoperative dry continence (73% of group 3, 33% of group 2 and 25% of group 1). In most patients who were not dry postoperative video urodynamics suggested suboptimal outlet resistance overcome by a hyperactive detrusor. No patient had postoperative upper tract deterioration. CONCLUSIONS: These results suggest that concomitant enterocystoplasty should be critically considered for pediatric patients undergoing sling cystourethropexy.

[Health care reform in Chile]. / La reforma de la salud en Chile.

This is a document presented to the Chilean Academy of Medicine by the Health Minister, the economist Carlos Massad, First of all, he refers to the general context of the reform, that he considers a process and not a breakpoint. Afterwards, he enumerates the change task: a) to generate awareness of the change and to convert health in a State issue; b) to adequate programs to population's new health profile; c) to install new management instruments in the health system; d) to decentralize decisions and to promote the participation of beneficiaries; e) to establish incentives and to flexibilize the Health System and f) to introduce correctives to private health insurance. He believes that Chile must drift to a economical protection system for universal and solidary health events. The additional assurances that people wants to buy, must be delimited.

Symptomatic tumors affecting the urinary tract in children with neurofibromatosis.

PURPOSE: We determined the need for urological screening in children with neurofibromatosis. MATERIALS AND METHODS: Of 96 children with neurofibromatosis treated at our institution 6 (6.2%) had a symptomatic tumor that affected the urinary tract. RESULTS: There were 5 plexiform neurofibromas and 1 prostatic rhabdomyosarcoma. Five children had a palpable abdominal mass and 3 required urinary diversion. CONCLUSIONS: Since most morbidity resulted because tumors were advanced by the time symptoms developed, we suggest that children with neurofibromatosis be screened annually with medical history, physical examination, urinalysis and serum chemistry studies for tumors that affect the urinary tract.

Transurethral puncture of ectopic ureteroceles in neonates and infants.

Ten neonates and infants with 11 ectopic ureteroceles prospectively underwent transurethral puncture as the primary form of therapy. Of the 10 patients 6 had a prenatal diagnosis of uropathy and 4 presented postnatally with urinary tract infection. One patient had bilateral single system ectopic ureteroceles and 9 had a single ectopic ureterocele in a duplex system. Significant associated ipsilateral and/or contralateral urological pathology was noted in addition to the ectopic ureterocele in 7 patients. Transurethral puncture adequately decompressed 10 of the 11 ectopic ureteroceles (91%) and improved drainage of nonureterocele moieties in 3 cases. Iatrogenic reflux was found in 3 of the 11 ureterocele ureters. Urinary tract infection developed in 6 infants (4 with fever). Of the 10 patients 8 (80%) eventually required secondary surgical intervention because of recurrent urinary tract infections, persistent or iatrogenic reflux, or unresolving hydronephrosis. Although transurethral puncture rarely constitutes definitive treatment for ectopic ureterocele, there appears to be immediate benefit in cases of bilateral hydronephrosis or significant ipsilateral lower pole hydronephrosis. Decompression of the ureterocele is reliably obtained but it seldom obviates the need for more definitive reconstruction.

The use of stomach in pediatric urinary reconstruction.

We report on 30 consecutive patients (mean age 9 years) who underwent gastrocystoplasty (21) or received a continent urinary reservoir with stomach (9). A successful outcome, defined as complete urinary continence for intervals greater than 3 hours, preservation or improvement of the upper tracts and renal function, and normal electrolyte and acid base balance, was achieved in 90% of the patients who received continent urinary reservoir and 72% of those who underwent gastrocystoplasty. Urodynamic data were obtained in 17 patients in the gastrocystoplasty group and 7 in the continent urinary reservoir group at a mean of 6 months postoperatively. Metabolic alkalosis associated with hypergastrinemia occurred in 2 children. Partial excision of the gastric segment was necessary in 1 patient refractory to medical treatment.

Acute hemodynamic and endocrinological effects of partial fetal bladder obstruction.

The pathophysiology of fetal urinary obstruction has not been elucidated. Using a unique, reproducible and easily reversible animal preparation, we studied the acute hemodynamic and endocrinological responses to partial fetal bladder obstruction in 16 ovine fetuses at 115 days of gestation (term 147 days). After partial obstruction blood pressure and renal weight increased significantly for at least 72 hours. Renal blood flow trended upwards, particularly from 24 to 72 hours, although this change was not statistically significant. Plasma renin activity was significantly increased during the first 24 hours after obstruction but it returned to baseline thereafter. Plasma cortisol or catecholamine concentrations remained unchanged. The time course and pattern of hemodynamic changes in this fetal sheep preparation of partial urinary obstruction differ significantly from those reported in other preparations.

The pharmacokinetics of intravesical and oral oxybutynin chloride.

In 8 children with cystometric evidence of bladder instability and marked systemic side effects to oral oxybutynin we investigated the efficacy of intravesical instillation and compared the pharmacokinetics of both routes of delivery. In addition, 4 healthy dogs underwent intravesical instillation for pharmacokinetic studies. Intravesical oxybutynin was well tolerated, efficacious and rapidly absorbed, resulting in plasma concentrations markedly higher than after oral administration. In only 2 patients did this method of instillation result in side effects, and both had previously undergone bladder augmentation. This lack of significant systemic side effects despite high plasma concentrations suggests that a metabolite may be generated after oral administration that is responsible for the side effects. These studies demonstrate that the mode of administration affects the mechanism of action, side effects, pharmacokinetics and metabolism of oxybutynin, and that intravesical instillation is clinically effective and results in minimal side effects.

Morphology and histochemistry of infant testes in the prune belly syndrome.

Testicular biopsy samples from 3 boys 5.5, 6 and 7 months old with the prune belly syndrome and intra-abdominal testes were examined morphologically and phenotypically for the presence of alkaline phosphatase. Findings were compared with those in age-matched autopsy controls. All patient specimens demonstrated atypical germ cells with large nuclei and prominent nucleoli, and intense alkaline phosphatase staining localized to the cytoplasmic membrane. The presence of these testicular abnormalities suggests that a developmental arrest is fundamental to the pathogenesis of the undescended testes associated with the prune belly syndrome. The similarity of the histological appearance of these testes to that of intratubular germ cell neoplasia suggests that long-term followup of these patients for the development of invasive germ cell tumors is important.

Contralateral intralobar nephrogenic rests: possible confusion with bilateral Wilms tumor.

We report 2 cases of unilateral Wilms tumor associated with contralateral intralobar nephrogenic rests. This disease complex may be confused with bilateral Wilms tumor, which may alter therapeutic decision-making.

Collagen and elastin in the normal fetal bladder.

The development of muscle, collagen and elastic fibers was studied histologically in 15 human fetal bladder specimens. Muscle thickness progressively increased and the relative collagen content in the muscle decreased during gestation. The ratio of thick-to-thin collagen fibers also decreased, whereas elastic fibers increased. These findings document the normal process of maturation of the fetal bladder and serve as a basis for comparison with congenitally obstructed fetal bladders.

Collagen and elastin in the obstructed fetal bladder.

Histological findings of muscle, collagen and elastin in obstructed fetal bladders were compared with those of age-matched controls. Muscle thickness was markedly increased, however, the relative collagen content in the muscle was decreased. The ratio of thick-to-thin collagen fibers was markedly increased as was the amount of elastin. These findings suggest that the ratio of thick collagen to elastin has an important role in determining the compliance of the obstructed fetal bladder.

Organ preservation in the management of pelvic rhabdomyosarcoma.

The role of exenterative surgical therapy in pelvic rhabdomyosarcoma has been progressively diminishing with the increasing effectiveness of combination chemotherapy. Cooperative studies have demonstrated that, in most instances, the initial surgical procedure should consist of a thorough examination under anesthesia and a biopsy of the mass. Surgery should be repeated to evaluate the therapeutic response to chemotherapy (with or without radiation treatment) so that radical resection, when necessary, is not unduly delayed. In some instances, patients who responded only partially to treatment will, with limited surgical excision, demonstrate a complete response on pathologic examination. The late effects of this multidisciplinary treatment plan must be studied further and long-term follow-up for these children is imperative.