The development of camptothecin analogs in childhood cancers.

Camptothecin analogs, agents that target the intranuclear enzyme topoisomerase I, represent a promising new class of anticancer drugs for the treatment of childhood cancer. In preclinical studies, camptothecins, such as topotecan and irinotecan, are highly active against a variety of pediatric malignancies including neuroblastomas, rhabdomyosarcomas, gliomas, and medulloblastomas. In this paper, we review the status of completed and ongoing clinical trials and pharmacokinetic studies of camptothecin analogs in children.

Protein synthesis costs could account for the tissue-specific effects of sub-lethal copper on protein synthesis in rainbow trout (Oncorhynchus mykiss).

This study investigates protein synthesis, following exposure to sub-lethal Cu, in rainbow trout in vivo and in vitro. The investigation has two aims: to determine if perturbations in protein synthesis, compared with other physiological changes, are a biomarker of Cu pollution and to evaluate the most productive role of cellular models in ecotoxicology. Protein synthesis rates were measured by labelling with 3H-phenylalanine.

Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates.

Purpose: Gemcitabine (dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against both leukemias and solid tumors. Pharmacokinetic studies of gemcitabine have been performed in both adults and children but to date there have been no detailed studies of its penetration into cerebrospinal fluid (CSF). The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate.

Introduction: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.

Treatment controversies in medulloblastoma.

Medulloblastoma, the most common primary malignant brain tumor in children, is a radiosensitive and chemosensitive tumor. Nevertheless, medulloblastoma remains a management challenge for the clinical oncologist, because the optimal sequence and dosage for each treatment modality has not yet been defined. In addition, effective management strategies for medulloblastoma may result in profound neuroendocrine and neuropsychologic sequelae.

Intrathecal chemotherapy.

An unforeseen consequence of improved disease-free survival in many hematologic and solid tumor malignancies has been an increase in the incidence of disease recurrence in the leptomeninges. The recognition of the central nervous system (CNS) as a unique 'sanctuary' site has resulted in the development of therapeutic strategies specifically directed at the leptomeninges. Although therapeutic strategies have been successful in the prevention and treatment of CNS leukemia, there are still a paucity of therapeutic options for patients with neoplastic meningitis due to solid tumors or recurrent CNS leukemia.

A phase I study of irinotecan in pediatric patients: a pediatric oncology group study.

A Phase I trial of irinotecan was performed to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the incidence and severity of other toxicities in children with refractory solid tumors. Thirty-five children received 146 courses of irinotecan administered as a 60-min i.v.

Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.

Purpose: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys.

Patients And Methods: We administered Rasburicase intravenously, at 0.15 or 0.

Phase II trial of pyrazoloacridine in children with solid tumors: a Pediatric Oncology Group phase II study.

Purpose: Pyrazoloacridine (PZA), a rationally synthesized deoxyribonucleic acid (DNA) binding agent that preferentially inhibits ribonucleic acid rather than DNA synthesis, is active against hypoxic and noncycling tumor cells and has greater in vitro activity against a broad range of human solid tumor lines than against the L1210 murine leukemia line. The Pediatric Oncology Group conducted a phase II study to determine the activity of PZA administered as a 3-hour infusion.

Patients And Methods: The activity of PZA was evaluated in patients with a variety of childhood solid tumors including rhabdomyosarcoma, Ewing sarcoma/peripheral neuroectodermal tumor, neuroblastoma, osteogenic sarcoma, Wilms tumor, or other solid tumors (excluding brain tumors).

Modified procedure for implantation of subcutaneous central venous access devices in macaques (Macaca mulatta).

A nonhuman primate model comprising adult male rhesus monkeys (Macaca mulatta) with chronically indwelling subcutaneous central venous access devices provides a unique opportunity to determine plasma pharmacokinetics of new drugs such as anticancer and anti- retroviral agents. The central venous access we use is a low-profile, single-septum, titanium port that is attached to a radiopaque, indwelling catheter; the catheter is implanted in an internal jugular vein. A common complication following placement of the venous access device was migration of the catheter tip.

Clinical pharmacology of encapsulated sustained-release cytarabine.

Background: The therapeutic effectiveness of chemotherapy is often limited by the inability to sustain cytotoxic concentrations at the tumor site. Cytarabine liposome injection (DepoCyt), a sterile, injectable suspension of the antimetabolite cytarabine, encapsulated into multivesicular, lipid-based particles, has been developed to improve the treatment of neoplastic meningitis (NM) through sustained release of cytarabine.

Objective: To review the pharmacokinetics, efficacy, and safety of intrathecal DepoCyt for the treatment of NM secondary to lymphoma or solid tumors.

Scaling properties of the frontal sinus in the African great apes--a clue to the role of the human paranasal sinuses.

The biology of scaling (allometry) can prove a useful tool in comparative anatomical studies. Amongst primates only the African Great Apes and Man possess a frontal sinus. The aim of this study was to identify the allometric properties of the frontal sinus in order to gain clues as to the role of the human paranasal sinuses.

CT scanning in "second look" combined approach tympanoplasty.

One of the main disadvantages of intact canal wall mastoid surgery for cholesteatoma is the necessity of the "second look". The morbidity of a second procedure can be reduced, however, with the aid of a rigid endoscope. Fifty-five consecutive patients undergoing a re-exploration were included in this study.

Neoplastic meningitis: diagnosis and treatment considerations.

Neoplastic meningitis is an increasingly recognized complication of advanced metastatic cancer and, if left undiagnosed or untreated, is characterized by rapid neurologic deterioration and death. Thus, the diagnosis and treatment of neoplastic meningitis present challenges for the clinical oncologist. The diagnosis of neoplastic meningitis is based on clinical signs and symptoms, laboratory analysis of cerebrospinal fluid to determine cell count and cytology, and analysis of neuroimaging studies for evidence of leptomeningeal or cranial nerve enhancement.

Pharmacokinetics and cerebrospinal fluid penetration of CI-994 (N-acetyldinaline) in the nonhuman primate.

CI-994 is a substituted benzamide derivative that has demonstrated significant antitumor activity in vitro and in vivo against a broad spectrum of murine and human tumor models. Its mechanism of action is still unknown but seems to be novel compared with existing anticancer drugs. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of CI-994 in nonhuman primates.

Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration.

Purpose: Intrathecal methotrexate achieves high concentrations in cerebrospinal fluid (CSF), but drug distribution throughout the subarachnoid space after an intralumbar dose is limited. The objective of this study was to quantify methotrexate distribution in CSF after intraventricular and intravenous administration and to identify factors that influence CSF distribution.

Methods: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received methotrexate by bolus injection (0.

Phase I and pharmacokinetic study of CI-980 in recurrent pediatric solid tumor cases: a Pediatric Oncology Group study.

To establish the maximum tolerated dosage (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetic parameters of CI-980, a novel tubulin binder, in children with solid tumors refractory to standard therapy. Patients 21 years of age or younger with adequate nutritional, hematopoietic, renal, and hepatic function were eligible. The patient must not have been pregnant.

The surgical management of the pars tensa retraction pocket in the child--results following simple excision and ventilation tube insertion.

Retraction pockets of the pars tensa formed due to poor mesotympanic ventilation can result in chronic infection, ossicular damage and even acquired cholesteatoma. A diversity in opinion exists as to the best surgical treatment of an established retraction pocket. This paper presents a consecutive prospective series of 39 ears managed over the last 4 years by means of simple excision and insertion of a middle ear ventilation tube.

Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy-thioguanine.

Thiopurine antimetabolites have been in clinical use for more than 40 years, yet the metabolism of thiopurines remains only partially understood. Data from our previous pediatric phase 1 trial of continuous i.v.

An assessment of the value of the preoperative computed tomography scans prior to otoendoscopic 'second look' in intact canal wall mastoid surgery.

'Second look' surgery following primary intact canal wall mastoid surgery for cholesteatoma is considered mandatory for most cases in modern otological practice. The morbidity of the second look can be reduced by the use of the rigid otoendoscope. Forty-three patients undergoing 'second look' surgery were studied with an average age of 24.

Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: a collaborative Pediatric Oncology Branch, National Cancer Institute and Children's Cancer Group trial.

Neutropenia is the dose-limiting toxicity of docetaxel in children. This Phase I trial was designed to determine the maximum tolerated dose, the dose-limiting toxicities, and the incidence and severity of other toxicities of docetaxel with filgrastim (G-CSF) support in children with refractory solid tumors. Docetaxel was administered as an i.

Neonatal stridor in association with herpes simplex infection of the larynx.

Herpes simplex virus (HSV) infection in the neonatal period may be confined to the eyes, skin and upper aerodigestive tract or may be widely disseminated to other organs, with particular recognition of involvement of the central nervous system (CNS) causing herpes encephalitis (Whitley et al., 1980a, b; Andersen, 1987). Primary laryngeal HSV infection is extremely uncommon.

Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates.

Purpose: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir.