Sentinel nodes outside lymph node basins in patients with melanoma.

BACKGROUND: Lymphoscintigraphy occasionally reveals hot spots outside lymph node basins in patients with melanoma. The aim of this study was to evaluate such abnormally located hot spots. METHODS: Sentinel node biopsy was studied prospectively in 379 patients with clinically localized cutaneous melanoma. One day after lymphoscintigraphy, sentinel node biopsy was performed guided by vital blue dye and a gamma ray detection probe. RESULTS: Persisting hot spots outside the regional node basins were seen in 25 patients (6.6 per cent). Several specific drainage patterns were discerned. In five patients, aberrant sentinel nodes were not explored. The hot spot represented a lymphangioma in two patients. Radioactive lymph nodes were identified in the remaining 18 patients (4.7 per cent). Four patients had metastasis in one of these aberrant lymph nodes. CONCLUSION: Sentinel nodes were found outside a lymph node basin in 5 per cent of patients. Particular drainage patterns exist. It is recommended to incorporate such sites in the late scintigraphy images and to pursue aberrant sentinel nodes, as they may be the only sites of metastasis.

Pharmaceutical development of a parenteral lyophilized formulation of the investigational antitumor neuropeptide antagonist [Arg6, D-Trp7,9, MePhe8]-Substance P [6-11].

The aim of this study was to develop a stable parenteral dosage form for the investigational cytotoxic drug [Arg6, D-Trp79,MePhe8]-Substance P [6-11] (Substance P Antagonist G; Antagonist G). Antagonist G bulk drug was structurally and analytically characterized. The drug exhibits excellent aqueous solubility, although relatively poor aqueous stability characteristics. Lyophilization was, therefore, selected as the manufacturing process. Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters which resulted in a stable, lyophilized formulation of Antagonist G. The prototype, containing 50 mg Antagonist G per vial, was found to be the optimal formulation in terms of solubility, length of the freeze-drying cycle, stability, and dosage requirements in the planned phase I clinical trials. Quality control of the freeze-dried formulation showed that the manufacturing process does not change the integrity of Antagonist G. Shelf life studies demonstrated that the formulation is stable for at least 3 years, when stored at 2-8 degrees C in a dark environment. Oxidative degradation products of Antagonist G were isolated and structurally characterized by mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy.

Wall dissection of the neourethra: a rare complication after hypospadias repair.

We present a rare complication causing severe infravesical obstruction after hypospadias repair after an initially successful double-faced island flap repair. The obstruction was caused by partial dissection of the epithelium of the urethral wall, comparable to intima dissection in an aortic aneurysm. To our knowledge, this type of urethral obstruction after a hypospadias repair has not been reported before.

Pharmaceutical development of a parenteral formulation of the investigational anticancer drug clanfenur.

A stable parenteral dosage form for the investigational cytotoxic drug clanfenur was designed, and the bulk drug was characterized by its nuclear magnetic resonance, mass spectrometry, infrared, and ultraviolet spectra. The 1H and 13C spectra show clanfenur to be a mixture of two stereoisomers. Because of poor solubility in aqueous solution and precipitation in co-solvent, surfactant, or emulsion systems, a two-pump infusion system was developed for intravenous administration. Clanfenur, solubilized in a Cremophor EL/ethanol (1:1, w/v) solution (concentration, 15 mg/mL), can be simultaneously infused with 5% dextrose infusion fluid. Total doses of up to 1,680 mg of clanfenur (and 56 g of Cremophor EL) theoretically can be administered to patients over a 6-hour period. From accelerated stability testing of clanfenur in the Cremophor EL/ethanol (1:1, w/v) formulation, a shelf life of 3.5 years at 4 degrees C and of 4 months at 25 degrees C is calculated.

Short- and mid-term outcome of different types of one-stage hypospadias corrections.

OBJECTIVE: This study is a retrospective analysis of the outcome of our one-stage hypospadias corrections. PATIENTS AND METHODS: In the period from August 1979 to January 1991, 316 boys less than 14 years of age underwent a one-stage hypospadias correction in our hospital. For 283 patients, data on the familial incidence, associated urological pathology, age at the time of operation, operation technique and follow-up were analyzed. RESULTS: The familial incidence in our study group was 9.4%, associated cryptorchidism was seen in 8.6%, kidney abnormalities in 1.8% and urethral valves in 0.4%. The majority (65.3%) of the children were operated on before the age of 3 years. The operation was performed according to Magpi, Mathieu, Devine-Horton, an onlay, and tube formation according to Duckett and the double-faced island flap procedure. Including all postoperative disturbances, urethral complications were seen in 18.1% and skin-related complications in 4.6% of the patients. CONCLUSION: Even in experienced hands the overall complications rate is relatively high, and additional problems can be expected in the future. It is important to provide adequate information on the procedures and possible complication to the parents. The final long-term outcome after puberty has to be awaited.

Early urethral obstruction sequence: a lethal entity?

Early urethral obstruction sequence (EUOS) is characterized by severe bladder distension by the end of the first trimester of pregnancy, resulting in renal dysplasia or hydronephrosis, oligohydramnios and subsequent lung hypoplasia. We reviewed the outcome of 18 fetuses with suspected EUOS. The mean gestational age at the time of diagnosis was 15 weeks. In 1 fetus, a vesicoamniotic shunt was placed unsuccessfully. Pregnancy was terminated in 11 fetuses and 9 showed signs of pulmonary hypoplasia and severe renal disease on autopsy. In 3 cases, the autopsy material could be evaluated. Premature delivery occurred in 2 patients, and 5 chose to deliver at term. All 7 fetuses died soon after birth because of respiratory failure and lung hypoplasia; renal abnormalities were also found on autopsy. Since it is currently not clear whether prenatal intervention will prevent renal dysplasia and it is not known how early it should be done to prevent pulmonary hypoplasia, we believe that termination of pregnancy should be discussed when EUOS is suspected.

Purity determinations in the bulk drug of the novel indoloquinone antitumor agent EO9.

The pharmaceutical development of the investigational cytotoxic drug EO9 included the structural characterization of the bulk drug by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS) and infrared (IR) spectroscopy, and analytical characterization by high-performance liquid chromatography and ultraviolet/visible spectrophotometry. The presence of impurities in the bulk drug was investigated. The intermediates in the synthesis of EO9 were structurally characterized by NMR spectroscopy and MS, and analytically characterized by HPLC analysis with photodiode array (PDA) detection. All of the intermediates were below their limits of detection in EO9 bulk drug. The amounts of residual organic solvents were determined by gas chromatography. Methanol and ethanol were detected, but the amounts present did not exceed the limits as set in the United States Pharmacopeia XXII.

Endoscopic intrauterine fetal therapy: a monkey model.

OBJECTIVES: Prenatal ultrasonographic investigations have led to an increasing number of prenatally detected abnormalities, of which a large number involves the urogenital tract. This study was performed to evaluate if endoscopic intra-amniotic access is possible in primates. METHODS: In 10 midtrimester rhesus monkeys (Macaca mulatta), endoscopic intrauterine fetoscopy was performed with three access cannulas. Using a Seldinger technique, a vascular access system, and a pediatric laparoscopy set, intra-amniotic inspection was attempted. Fetal growth throughout pregnancy was monitored by ultrasonographic measurements of fetal biometry. RESULTS: Intrauterine access could successfully be achieved in 10 rhesus monkeys with three cannulas. After partial amniotic fluid exchange, adequate fetoscopy was always possible. Two monkeys aborted on the second and sixth postoperative days. Serial ultrasonographic investigations for fetal biometry showed no disturbance of the intrauterine growth patterns in the remaining 8 monkeys. CONCLUSIONS: We currently conclude that the rhesus monkey model for experimental intrauterine endoscopic surgery may be suitable for study of the developmental abnormalities of the genitourinary tract.

The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain.

PURPOSE: The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated. METHODS: Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX. RESULTS: MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250%). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65%). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain. CONCLUSIONS: Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.

Bilateral ureteral obstruction after appendectomy in children.

Five cases of bilateral ureteral obstruction after appendicectomy are presented. All five patients were boys (age range, 9 to 15 years). All of them had had severe appendicitis. Based on the urethrocystoscopy findings, edema of the posterior bladder wall appeared to be the cause of obstruction of both distal ureters. This is confirmed by the immediate recovery of renal function after installation of bilateral uretercatheters. It is known that contamination of the peritoneal cavity can occur by organisms leaking from a gangrenous or perforated appendix. This can cause localized inflammatory edema of the posterior bladder wall. It is remarkable that through ultrasound investigation, only mild to moderate dilatation of the urinary tract was observed. An explanation can be obtained from animal models, wherein acute obstruction of the ureter leads only to a transient increase in ureteral pressure, followed by a decline toward the preobstruction level. It is important to be aware that this complication can occur after appendectomy; bilateral uretercatheters can be installed, and irreversible renal damage can be avoided.

The influence of formulation excipients on the stability of the novel antitumor agent carzelesin (U-80,244).

The stability of carzelesin in a polyethylene glycol 400 (PEG 400)/absolute ethanol/polysorbate 80 (Tween 80) (6:3:1, v/v/v) formulation (PET formulation) was investigated as a function of the inter-batch variability of the three excipients. Twenty different PET formulations were tested and the stability of carzelesin in the PET formulation was found to be influenced by the type of PEG 400 used. Subsequent investigations showed that the pH of PEG 400, and consequently the pH of the PET formulation, was responsible for the variable stability characteristics of carzelesin in the PET formulation. The higher the pH of the PET formulation, the higher the rate of degradation of carzelesin in PET. The major degradation products were found to be U-76,073 and U-76,074.

[Congenital urethra valves; experiences in 73 children]. / Aangeboren urethrakleppen; ervaringen bij 73 kinderen.

OBJECTIVE: To inventory symptoms of children with urethral valves, and their prognosis. DESIGN: Descriptive. SETTING: Department of paediatrics and urology, University of Nijmegen. METHODS: Symptoms were evaluated from clinical data and interviews of the parents of 73 patients. The glomerular filtration rate (GFR) was calculated from the serum creatinine level by the method of Counahan. RESULTS: Symptoms indicating an urethral obstruction, e.g. diminished urinary jet, were rare (20% of the children). General symptoms prevailed: vomiting, anorexia, growth failure, fever. After 2 years 11 out of 53 children had a GFR < 25 ml/min/1.73 m2 body surface area. CONCLUSION: Specific symptoms indicating an urethral obstruction are rare. The glomerular filtration is often diminished. There are no measures to prevent loss of renal function.

Paratesticular rhabdomyosarcoma.

Even though rhabdomyosarcoma is the most common soft tissue sarcoma in children, accounting for 5-10% of all malignant disease in children under 15 years of age, so few cases are seen in a single institution that only the combined efforts of multicentre prospective trials made it possible fro adequate treatment schedules to be devised. Thank to this cooperation, survival rates have increased dramatically in recent decades; risk factors have been identified and treatment can now be adapted accordingly. This is especially true for the paratesticular rhabdomyosarcoma (PTRM), which now has a good prognosis in all stages. The striking similarity of tumor behavior and metastatic pathways to those in germ-cell tumors in young male adults can provide us with more extensive data derived from a much larger group of patients. Recent data are gathered and evaluated in this review. Only in this way will it be possible to eliminate all treatment modalities known to be followed by severe sequelae, thus avoiding exposure of the patients to a therapy that carries more risks than the primary tumor itself.

Pediatric urology and the daily medical practice: way apart?

This is a study about the current status of knowledge and level of insight in treatment possibilities of pediatric urological diseases in daily practice of Dutch general practitioners (GPs). A questionnaire was mailed to GPs with questions concerning the structure of their medical practice, the localization, the received education in pediatric urology and knowledge of this subspeciality. Also, questions were asked about their current knowledge and first choice of treatment for maldescensus testis, urinary tract infections, enuresis nocturna and congenital abnormalities. The 995 forms that were returned, representing 1,457 GPs, are discussed. New developments in diagnostic procedures and treatment possibilities should be reflected in the exchange of information between GPs and (sub)specialists. However, before changes can be realized, the current knowledge and opinions should be known. This study investigates the current opinion of GPs of different pediatric urological diseases. Additionally, the incidence and current state of the art in diagnosis and treatment are discussed.

Measurement of the blood supply to the abdominal testis by means of near infrared spectroscopy.

Cryptorchidism is the most common male sexual disorder. In the case of an abdominal testis there is no objective criterion to choose between autotransplantation or orchiopexy after ligation of the spermatic vessels with subsequent development of collateral blood supply. By combining near infrared spectroscopy (NIRS) with pulse oximetry the active testicular blood volume (ATBV) before and after occlusion of the spermatic vessels can be calculated in an animal model. NIRS is a noninvasive continuous optical technique that measures tissue oxygenation and hemodynamics. Ten boars with one non-palpable testis each were selected. The spermatic vessels and vas deferens were separately prepared and atraumatic occluders were placed around the vessels. ATBV was measured before and after occlusion of the spermatic vessels. The calculated ATBV was 18.3 +/- 2.3 ml/100 g of testicular tissue, not corrected by division by the path length factor, accounting for light scattering in the tissue. In 5 of 10 boars no significant ATBV was found after occlusion of the spermatic vessels, suggesting subsequent atrophy. NIRS combined with pulse oximetry provides us with reproducible quantification of ATBV. The method can be used to investigate the viability of a testis after (temporary) occlusion of the spermatic vessels.

Outcome analysis of the psychosexual and socioeconomical development of adult patients born with bladder exstrophy.

Since sonographic evaluation of the fetus became routine, prenatally established diagnosis of multiple or severe malformations raises the question of whether a pregnancy should be terminated. To answer this question properly, all aspects concerning the life of a child born with a serious malformation, such as exstrophy of the bladder, must be considered. Therefore, more than ever an evaluation of the quality of life of these patients is necessary to be able to make a solid based decision. We studied the psychosexual and socioeconomic development of 22 adult exstrophy patients (11 men and 11 women) by a standardized personal interview, evaluation of a standard performance test SCL-90 (symptom checklist 1990) and an adapted personality score test. The latter 2 tests are well established and provide reproducible results. Based on several large scale investigations, standard scores are available. Nine women (82%) and 10 men (91%) scored better or in accordance with the standard scores. Exstrophy of the bladder does influence the psychosexual and socioeconomic development. The quality of life is hardly ever considered so poor that termination of pregnancy is a realistic alternative.