Conduct of phase I trials in children with cancer

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.     

Transdermal absorption of clindamycin and tretinoin from topically applied anti-acne formulations in man

The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL(-1)) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL(-1). Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL(-1). The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake.     

Candida infection of a silicone metacarpophalangeal arthroplasty

Fungal infections following joint arthroplasty are extremely rare. Only 16 cases of Candida prosthetic infections have been reported, involving the hip, knee or shoulder joints. We report a case of a silicone metacarpophalangeal joint replacement complicated by a Candida albicans infection.     

Management guidelines for progressive chronic renal failure. New Zealand Nephrologists Consensus Group

Consensus guidelines are provided for the conservative management of adult patients with chronic and progressive renal failure, together with a brief review of the evidence relating to various treatable complications. Blood pressure control, diet, hyperlipidaemia, calcium and phosphate metabolism, anaemia and acidosis are considered.     

Nutrient flows in agriculture in The Netherlands with special emphasis on pig production

Annual nitrogen (N), phosphorus (P), and potassium (K) flows in agriculture in The Netherlands were identified and quantified in 1990, with special emphasis on pig production. Also, the effects that various management strategies in pig production have on NPK emission in 1990 were compared using a static deterministic simulation model. Ammonia emission from pig production in 1990 (60.9 Gg N) exceeded the defined target for the year 2000 (12.7 Gg N). Measures that affect volatilization of ammonia directly (i.e., introduction of low-emission stables, manure storage facilities, or manure application techniques) reduced ammonia emission most effectively. These measures, however, should be combined with a reduction in application of artificial N fertilizer to avoid an increase in N losses through leaching, run-off, or denitrification. Targets for ammonia emission in the year 2010 require a reduction in the pig population of 24 to 62%, in addition to implications of measures described in this article. National NPK losses in 1990 through leaching, run-off, or denitrification, predicted at 223.5 kg/ha for N, 32.7 kg/ha for P, and 67 kg/ha for K, exceeded government targets for the year 2010 (185 kg N/ha; 8.7 kg P/ha; norm not set for K). Reducing application of artificial NPK fertilizer reduced national NPK losses most effectively. For P, use of phytase and feeding pigs in accordance with their P requirements is required, in addition to limited use of artificial P fertilizer to meet targets for the year 2010. Hence, from an environmental point of view, pig production in The Netherlands is limited primarily by ammonia emission targets for the year 2010.     

Oligonucleotide (GTG)5 as an epidemiological tool in the study of nontuberculous mycobacteria

Analysis of restriction fragment length polymorphisms in the genome of Mycobacterium tuberculosis (DNA fingerprinting) has proved to be a useful epidemiological tool in the study of tuberculosis within populations or communities. However, to date, no similar method has been developed to study the epidemiology of nontuberculous mycobacteria (NTM). In this communication, we report that a simple oligonucleotide repeat, (GTG)5, can be used to accurately genotype all species and strains of NTM tested. We suggest that this technology is an easily applied and accurate tool which can be used for the study of the epidemiology of NTM.     

Organization and development of facial motor neurons in the kreisler mutant mouse

The adult facial nerve contains the axons from two populations of efferent neurons. First, the branchiomotor efferent neurons that innervate the muscles of the second arch. These neurons project out of the hindbrain in the motor root and form the facial motor nuclei. Second, the preganglionic efferent neurons that innervate the submandibular and pterygopalatine ganglia. These neurons project from the hindbrain via the intermediate nerve and form the superior salivatory nucleus. The motor neurons of the facial nerve are known to originate within rhombomeres 4 and 5. In the kreisler mouse mutant there is a specific disruption of the hindbrain rhombomeres 5 and 6 appear to be absent. To investigate changes in the organization of the facial motor neurons in this mutant, we have used lipophilic dyes to trace the facial motor components both retrogradely and anterogradely. As expected, facial motor neurons are missing from rhombomere 5 in this mutant. In addition, the loss of these neurons correlates with the specific loss of the superior salivatory nucleus. In contrast, the branchiomeric neurons, that originate in rhombomere 4, appear to develop normally. This includes the caudal migration of their cell bodies forming the genu of the facial nerve. Our studies confirm that rhombomeres are critical to hindbrain development and that they are the fundamental unit at which motor neurons are specified.     

Results of Watson-Jones ankle reconstruction for instability. The influence of articular damage

We reviewed 32 ankles in 30 patients at an average of five years after a Watson-Jones tenodesis. All but one patient had had ankle pain before operation and 19 had had clicking, catching, or locking of the ankle. Eleven of these had an ankle arthrotomy at the time of ligament reconstruction for intraarticular pathology. At review seven of 23 ankles had a significant decrease in ankle motion, and five in subtalar motion, but only two were unstable on examination. Twenty-one ankles, however, caused some pain on activity and nine were tender on palpation. These findings indicate intra-articular degeneration or injury rather than simple instability. Radiographs of 16 ankles showed good varus and anterior-drawer stability. Seven had talocrural osteoarthritis, but only four showed grade-1 subtalar osteoarthritis. We found no correlation between follow-up time and long-term results. The Watson-Jones tenodesis provides good rotational and lateral ankle instability and does not appear to lead to subtalar degeneration.