Phase I study of topotecan for pediatric patients with malignant solid tumors

PURPOSE: To determine the dose-limiting toxicity and potential efficacy of topotecan in pediatric patients with refractory malignant solid tumors. PATIENTS AND METHODS: In this phase I clinical trial, 27 patients received topotecan 0.75-1.9 mg/m2 by continuous intravenous infusion daily for 3 days. Fifty-three treatment courses were given to these patients. RESULTS: Myelosuppression was the dose-limiting toxicity at levels of 1.3 to 1.9 mg/m2 for 3 days, requiring significant support with transfused packed RBCs and platelets. Myelosuppression was variable in severity at the 1.0-mg/m2 dosage level; thus, additional patients were treated with this dosage, followed by human recombinant granulocyte-colony stimulating factor (G-CSF). Other toxicities were not significant. One patient with neuroblastoma had a complete response that lasted for 8 months. Stable disease activity was recorded for other patients with neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma. Pharmacokinetic studies showed that topotecan plasma concentrations ranged from 1.6 to 7.5 ng/mL during infusions of 1.0 mg/m2/d, and that there was a biphasic plasma distribution with a mean terminal half-life of 2.9 +2- 1.0 hours. CONCLUSION: Topotecan is a promising anticancer agent that deserves phase II testing in pediatric solid tumors. We recommend that pediatric phase II topotecan trials use 1.0 mg/m2/d for 3 days as a constant intravenous infusion, followed by G-CSF for 14 days, and that these treatment courses be repeated every 21 days.     

Pseudarthroses of the bones of the extremities of gunshot origin

The causes of formation of false joints of shot origin are given in the present paper. The treatment included internal and transosseous osteosynthesis. In presence of fistula form of the chronic osteomyelitis preliminary necr- and sequestrectomy carried out. The shortening was resected by bone osteotomy and distraction by apparatus combined with false joint compression. The most frequent appeared to be purulent complications and nonremoved extremity deformity. Adhesion was achieved after 151 operation.     

Disorders of visuo-spatial attention in patients with unilateral brain damage

Visuo-spatial inattention (VSI) was examined in 390 patients with ischemic insult to the right or left cerebral hemispheres. VSI was revealed in 44 out of 80 patients with right parietal lobe damage and in 30 out of 70 subjects with right occipital lobe injury. Only one patient out of 100 with left hemisphere injury has shown the signs of VSI. These data confirm the suggestion that the right parietal and occipital regions are crucial for visuo-spatial attention, whereas the left hemisphere is of minor import.     

Support systems and stress reduction among workers caring for dependent parents

This study investigated the impact of three types of support--from family and friends, the workplace, and community services agencies--on the perceived stress and health outcomes of 133 employed caregivers of dependent parents. The stressor-support-stress-reaction model guided the research. Support from family and friends and community agencies was found to buffer the negative impact of caregiving and work and family role strain, and a supportive work environment was one predictor of lessened physical strain.     

The stress-protective effect of a new derivative of n-3-polyunsaturated fatty acids

It has been established that prophylactic oral administration of the new derivative of n-3 polyunsaturated fatty acids--P-55 in a daily dose of 0.2 g/kg during 30 days prevents some morphological and physiological manifestations of the chronic stress-syndrome in white rats. There were normalized body and some internal organs weights, content and distribution of ascorbic acid in the adrenal tissue; decreased intensity of gastric ulcerogenesis. The behaviour of animals became more quiet. It is concluded that the preparation P-55 has a stress-protective effect during its prophylactic administration.     

Role of proteolysis in apoptosis: involvement of serine proteases in internucleosomal DNA fragmentation in immature thymocytes

Three chemically distinct serine, but not cysteine, protease inhibitors (phenylmethylsulphonyl fluoride, N-tosyl-L-phenylalanylchloromethyl ketone and 3,4-dichloroisocoumarin) prevented, in a dose-dependent manner, the characteristic apoptotic internucleosomal DNA cleavage (DNA ladder) typically observed in thymocytes in response to dexamethasone and teniposide VM-26. This effect was not the result of a direct inhibition of the Ca2+,Mg(2+)-dependent endonuclease, since oligonucleosomal DNA cleavage occurred in the presence of these inhibitors in isolated nuclei. The proteolytic step occurred at a very early stage of apoptosis, and preincubation of thymocytes with the inhibitors before dexamethasone or teniposide VM-26 were added irreversibly suppressed ladder formation. This implied that the cellular effector(s) of these compounds preexisted and were not resynthesized in response to the inducers of apoptosis. Serine protease inhibitors also suppressed apoptotic cell shrinkage and complete nuclear collapse, suggesting that these morphological changes were directly related to internucleosomal fragmentation of DNA. However, the serine protease inhibitors did not prevent high molecular weight DNA cleavage (> 50 kilobases) that preceded the ladder formation and thymocytes still died by apoptosis. This supported the view that internucleosomal DNA cleavage, considered to be the biochemical marker of apoptosis, might in fact be a late and dispensable step and that the newly described high molecular weight DNA cleavage might be a better indicator of apoptosis.     

Effect of dietary alpha-linolenic acid and its ratio to linoleic acid on platelet and plasma fatty acids and thrombogenesis

The effect of dietary alpha-linolenic acid (18:3n-3) and its ratio to linoleic acid (18:2n-6) on platelet and plasma phospholipid (PL) fatty acid patterns and prostanoid production were studied in normolipidemic men. The study consisted of two 42-d phases. Each was divided into a 6-d pre-experimental period, during which a mixed fat diet was fed, and two-18 d experimental periods, during which a mixture of sunflower and olive oil [low 18:3n-3 content, high 18:2/18:3 ratio (LO-HI diet)], soybean oil (intermediate 18:3n-3 content, intermediate 18:2/18:3 ratio), canola oil (intermediate 18:3n-3 content, low 18:2/18:3 ratio) and a mixture of sunflower, olive and flax oil [high 18:3n-3 content, low 18:2/18:3 ratio (HI-LO diet)] provided 77% of the fat (26% of the energy) in the diet. The 18:3n-3 content and the 18:2/18:3 ratio of the experimental diets were: 0.8%, 27.4; 6.5%, 6.9; 6.6%, 3.0; and 13.4%, 2.7, respectively. There were appreciable differences in the fatty acid composition of platelet and plasma PLs. Nevertheless, 18:1n-9, 18:2n-6 and 18:3n-3 levels in PL reflected the fatty acid composition of the diets, although very little 18:3n-3 was incorporated into PL. Both the level of 18:3n-3 in the diet and the 18:2/18:3 ratio were important in influencing the levels of longer chain n-3 fatty acid, especially 20:5n-3, in platelet and plasma PL. Production of 6-keto-PGF1 alpha was significantly (P < 0.05) higher following the HI-LO diet than the LO-HI diet although dietary fat source had no effect on bleeding time or thromboxane B2 production.(ABSTRACT TRUNCATED AT 250 WORDS)