Primary testicular and paratesticular tumors of childhood

Testicular and paratesticular neoplasms are uncommon tumors of childhood. Consequently, the experience gained with regard to their optimal management is limited in any given children's cancer centre. Here we review the classification, diagnosis, and staging of testicular and paratesticular neoplasms and subsequently discuss the more frequently occurring ones: germ cell tumors, gonadal stromal tumors, gonadoblastoma, tumors of the supporting tissue, lymphomas and leukemias, tumor-like lesions, secondary tumors, and tumors of the adnexa. © 1994 Wiley-Liss, Inc.     

Intravenous Cereport (RMP-7) Enhances Delivery of Hydrophilic Chemotherapeutics and Increases Survival in Rats with Metastatic Tumors in the Brain

Purpose. The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. Methods. Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the hydrophilic (carboplatin) chemotherapeutic agents, as well as the large hydrophilic marker, 70 kDa dextran. Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorelbine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone. Results. Cereport enhanced the uptake of carboplatin and dextran, but not paclitaxel or carmustine. The pattern of Cereport's uptake effect with carboplatin revealed that Cereport selectively increased the proportion of highly permeable regions. Survival was significantly enhanced when Cereport was combined with either carboplatin, vinorelbine, or gemcitabine, but not carmustine, compared to each chemotherapeutic agent alone. Conclusions. These data provide the first evidence that Cereport, or any receptor-mediated approach intended to enhance the permeability of the blood-brain tumor barrier, can increase the delivery hydrophilic drugs to metastatic tumors in the brain, increasing survival in tumor-bearing rats.     

Time-dependent influence of sensorimotor set on automatic responses in perturbed stance

 These experiments tested the hypothesis that the ability to change sensorimotor set quickly for au-tomatic responses depends on the time interval between successive surface perturbations. Sensorimotor set refers to the influence of prior experience or context on the state of the sensorimotor system. Sensorimotor set for postural responses was influenced by first giving subjects a block of identical backward translations of the support surface, causing forward sway and automatic gastrocnemius responses. The ability to change set quickly was inferred by measuring the suppression of the stretched antagonist gastrocnemius responses to toes-up rotations causing backward sway, following the translations. Responses were examined under short (10–14 s) and long (19–24 s) inter-trial intervals in young healthy subjects. The results showed that subjects in the long-interval group changed set immediately by suppressing gastrocnemius to 51% of translation responses within the first rotation and continued to suppress them over succeeding rotations. In contrast, subjects in the short-interval group did not change set immediately, but required two or more rotations to suppress gastrocnemius responses. By the last rotation, the short-interval group suppressed gastrocnemius responses to 33%, similar to the long-interval group of 29%. Associated surface plantarflexor torque resulting from these responses showed similar results. When rotation and translation perturbations alternated, however, the short-interval group was not able to suppress gastrocnemius responses to rotations as much as the long-interval group, although they did suppress more than in the first rotation trial after a series of translations. Set for automatic responses appears to linger, from one trial to the next. Specifically, sensorimotor set is more difficult to change when surface perturbations are given in close succession, making it appear as if set has become progressively stronger. A strong set does not mean that responses become larger over consecutive trials. Rather, it is inferred by the extent of difficulty in changing a response when it is appropriate to do so. These results suggest that the ability to change sensorimotor set quickly is sensitive to whether the change is required after a long or a short series of a prior different response, which in turn depends on the time interval between successive trials. Different rate of gastrocnemius suppression to toes-up rotation of the support surface have been reported in previous studies. This may be partially explained by different inter-trial time intervals demonstrated in this study. Received: 7 October 1997 / Accepted: 31 August 1998     

Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine: relevance to uridine rescue in chemotherapy

Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acyclouridine (PSAU) with 2′,3′,5′-tri-O-acetyluridine (TAU) on the levels of plasma uridine in mice. PSAU is a new lipophilic and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral uridine. TAU is a prodrug of uridine and a far superior source of uridine than uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the C_max and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma uridine concentration could be useful in the management of medical disorders that are remedied by administration of uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues. Received: 10 November 1999 / Accepted: 14 March 2000     

Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery

Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia, hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-trans-retinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5 min, and at 1, 2, 4, 6 and 24 h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5–17 h), lower peak serum concentrations (aerosol 71 ± 31 ng/ml, IT 68 ± 50 ng/ml), and lower liver levels (aerosol 111 ± 28 ng/g, IT 753 ± 350 ng/g) than the same dose administered IV (2 h, 838 ± 56 ng/ml, 4258 ± 1006 ng/g, respectively; P < 0.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing. Received: 17 September 1999 / Accepted: 14 April 2000     

Modulation of plasma uridine concentration by 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy

PURPOSE: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plasma uridine concentration as well as its ability to improve the bioavailability of oral uridine. PSAU is a new potent and specific inhibitor of uridine phosphorylase (Urd-Pase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. METHODS: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. RESULTS: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma uridine (2.6 +/- 0.7 microM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with uridine elevated the concentration of plasma uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (C(max)) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral uridine (7.7%) administered at 1,320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1,421 to 787 micromol/h x l and 273 micromol/h x l, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1,320 mg/kg uridine was used. CONCLUSION: The effectiveness of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.     

Allergic rhinitis: managing the adult spectrum.

With the general population increasing in age, clinicians will be seeing more elderly patients. Many present with bothersome rhinitis. A number of physiological and anatomic changes associated with age predispose the elderly population to develop rhinitis. A number of categories of rhinitis occur in elderly people and it is important to make the correct diagnosis. Appropriate therapy is available but the clinician must be wary of side effects, particularly to antihistamines and decongestants that may be more severe in elderly patients.     

Attentional functioning and white matter integrity among survivors of malignant brain tumors of childhood.

Children surviving treatment for malignant brain tumors commonly have problems maintaining their premorbid levels of intellectual development and academic achievement. Our group has been especially interested in the effects of treatment on normal appearing white matter (NAWM) on MRI and the influence of NAWM volumes on neurocognitive functioning. The present study assessed NAWM and attentional abilities among 37 long-term survivors of malignant brain tumors, ranging in age from 1.7 to 14.8 (Mdn = 6.5) years at diagnosis, who had been treated with cranial radiation therapy with or without chemotherapy 2.6 to 15.3 (Mdn = 5.7) years earlier. On the Conners' Continuous Performance Test, the Overall Index and 7 of the other 10 indices were significantly deficient compared to age- and gender-corrected normative values. After statistically controlling for the effects of age at diagnosis and time elapsed from treatment, 5 of the 8 indices were significantly associated with cerebral white matter volumes and/or specific regional white matter volumes of the prefrontal/frontal lobe and cingulate gyrus. No gender effects were observed. The results of the present study further support the contention that NAWM is an important substrate for treatment-induced neurocognitive problems among survivors of malignant brain tumors of childhood.     

Magnetic resonance imaging of non-tropical chyluria due to distal thoracic duct obstruction.

A 39-year-old white male with a history of subtotal thyroidectomywas referred because of intermittent nightly voiding of milkyurine for a period of 1 year, suggestive of