Randomized study of 13-cis retinoic acid v placebo in the myelodysplastic disorders

A double-blind, placebo-controlled randomized trial of 13-cis retinoic acid was performed to determine if the drug has a therapeutic effect in patients with myelodysplastic syndromes (MDS). Sixty-eight evaluable patients with MDS were randomized to receive a single, daily oral dose of either 13-cis retinoic acid (13-CRA, 100 mg/m2) or matching placebo. Treatment was continued, when possible, for a period of 6 months. Determination of response to treatment was based on clinical course, repeat bone marrow biopsies, and aspirates and blood counts (CBC) with WBC differential, platelet, and reticulocyte numbers at specified intervals. No significant difference was noted between the two treatment groups in response to test drug (P = .66). One patient (3%) in the 13-CRA group and two patients (6%) in the placebo group had a minor response. Approximately 30% of patients in both groups had progression of their disease, and progression-free survival was nearly identical. Greater than 90% of the patients receiving 13-CRA developed mild or moderate skin toxicity that was reversible with decreasing or discontinuing the drug. Our study did not find that 13-CRA exerts a beneficial therapeutic effect in patients with MDS.     

Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.     

4p16.3 haplotype modifying age at onset of Huntington disease

Huntington disease (HD) is caused by an expanded CAG repeat sequence in the HD gene. Although the age at onset is correlated to the CAG repeat length, this correlation only explains approximately half of the variation in onset age. Less variation between siblings indicates that the variation is, in part, explained by genetic modifiers. We analyzed polymorphic loci within or close to the HD gene on the HD chromosome in Danish HD patients. We found one specific haplotype segregating with later age at onset, compared with patients with similar CAG repeat length and another haplotype. The nine Danish families in the study carrying this haplotype most likely have a common founder. Several of the polymorphic loci displayed alleles that may be specific to the late-onset haplotype, implicating that from this study we cannot determine which of the loci tested (or other polymorphic loci in this chromosomal area) do in fact contain genetic modifiers of age at onset.     

Regressed retinopathy of prematurity: the relationship between clinical risk factors of the newborn period and regressed retinopathy of prematurity severity in a preterm born population of Stockholm county 1976-81

In a retrospective study, clinical risk factors of the neonatal period were correlated with the severity of regressed retinopathy of prematurity (ROP) in a population of preterm infants (bw less than 1500 g and or gestational age less than 33 weeks). At the age of 5-11 years 134 out of 528 preterm born infants (25.4%) were found to be under ophthalmic care. Reliable information on eye fundus status could be obtained in 105 of them. Regressed ROP was found in 61, the moderate form in 48 (9.1%) and the severe form in 13 (2.5%) patients. Twelve patients (2.3%) had visual acuity of less than 0.3 on the worst eye and two (0.4%) of these patients were blind from ROP. Twenty-four clinical factors of the newborn period were correlated with the severity of regressed ROP. The results suggest that long oxygen exposure in combination with other factors interfering with retinal vasotonus are associated with the degree of the disease developed.     

Donor site morbidity after harvest of free osteofasciocutaneous fibular flaps with an extended skin island

Since 1993, a total of 41 free osteofasciocutaneous fibular flaps with an extended skin island (average dimensions, 16.9 cm long [range, 12-22 cm] x 10.7 cm wide [range, -16 cm], or 180.8 cm [range, 112-352 cm ]) have been used in by the authors in various clinical applications. To evaluate donor site morbidity, the 41 patients involved were asked to answer a questionnaire and to present themselves for clinical and radiological examination. The subjective findings reported by these patients, and the examinations, showed that donor site morbidity was moderate. Apart from some occurrence of mild edema and pain, as well as modest motor weakness of the great toe, and deficiency of distal nervous segments, only 7 patients were found to have a slightly positive anterior drawer of the talus (anterior subluxation of the talus), but no instability. In conclusion, donor site morbidity after harvest of osteofasciocutaneous fibular flaps for different clinical indications, where extended skin islands were needed, is moderate.     

Effectiveness of alternative treatments for reducing potential viral contaminants from plasma-derived products

An issue of great importance and continuing concern with regard to all products derived from human plasma is their safety from potential contaminants in the source material from which they are purified. Since viral contaminants are a major safety consideration with these products, a number of different methods, including dry heating, vapor heating, filtration and nanofiltration, ultraviolet and gamma irradiation, pasteurization, solvent/detergent (S/D) treatment, sodium thiocyanate treatment, and chromatography (immunoaffinity, metal chelation, affinity, and ion exchange), have been developed to remove or inactivate potentially contaminating viruses. Pasteurization and S/D treatment have emerged as the dominant viral inactivation methods. Results summarized in this review demonstrate that pasteurization is the broadest and most rigorous currently available method for removal of potential viral contaminants from plasma-derived products. S/D treatment requires control over a large number of manufacturing parameters and has no ability to inactivate nonlipid-enveloped viruses. Pasteurization requires control over only a small number of manufacturing variables, is easily monitored, and remains effective even if deviations are encountered from specified protein and stabilizer concentrations and temperature. In addition, pasteurization is effective against a wide range of lipid- and nonlipid-enveloped viruses.