Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates

Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.     

Therapy of severe aplastic anemia in young adults and children with allogeneic bone marrow transplantation

During an 8-year period, 28 young adults (median age 27 years) and 30 children (median age 10 years) with severe aplastic anemia have received allogeneic bone marrow transplantation (BMT) from major histocompatibility locimatched sibling donors after preparation with cyclophosphamide and total lymphoid irradiation (TLI). All recipients were previously transfused. Comparison of post-bone marrow transplantation events in adults and children reveals equivalent median time to engraftment, median duration of hospitalization, median Karnofsky assessment of activity, and equivalent low rejection rate. Although the incidence of moderate and severe acute graft-v-host disease (GVHD) and of extensive chronic GVHD was greater in adults than in children, the projected survival at 4 years of adults (67%; 95% confidence interval [CI] 49% to 85%) and of children (73%; 95% CI 57% to 89%) was equivalent. All survivors are transfusion-free and have normal peripheral blood counts. One of 28 adults and 2 of 30 children have experienced rejection, and 1 of these patients survives after a second transplant. No malignancies have been identified following transplantation. An unexpectedly high incidence of hypothyroidism has been detected and may be attributable to preparation of recipients with TLI. Therapy of severe aplastic anemia with allogeneic BMT after preparation with cyclophosphamide and TLI offers a high rate of transfusion-free survival and a low rejection rate in previously transfused young adults and children.     

Summer-type relapsing fever (hypersensitivity pneumonitis) secondary to Cladosporium herbarum in the domestic environment

‘Summer-type relapsing fever’ is the most prevalent form of hypersensitivity pneumonitis in Japan. It is usually caused by hypersensitivity to Trichosporon cutaneum – a seasonal mould which thrives in homes with damp, decayed wood, damp mats and bedclothes. The disease has been rarely described outside Japan. We report the first documented case of summer-type hypersensitivity pneumonitis in Europe – in this case caused by hypersensitivity to the mould Cladosporium herbarum.     

Experimental systemic contact dermatitis from nickel: a dose-response study

Systemic contact dermatitis is usually seen as flare-up of previous dermatitis or de novo dermatitis similar to allergic contact dermatitis. Although systemic contact dermatitis from medicaments is a well-established entity, the existence of clinically relevant systemic reactions to oral nickel exposure, in particular systemic reactions to nickel in the daily diet, remains controversial. Several studies have shown that oral exposure to nickel can induce systemic contact dermatitis in nickel-sensitive individuals. In most of these studies, however, the exposure dose of nickel used has been considerably higher than the nickel content in the normal daily diet. The aim of the current investigation was to study dose-response dependency of oral exposure to nickel. In a double-blind, placebo-controlled oral exposure trial, 40 nickel-sensitive persons and 20 healthy (non-nickel-sensitive) controls were given nickel sulfate hexahydrate in doses similar to and greater than the amount of nickel ingested in the normal Danish daily diet. The nickel content in urine and serum before and after oral exposure was measured to determine nickel uptake and excretion. The influence of the amount of nickel ingested on the clinical reactions to oral exposure and on nickel concentrations in serum and urine was evaluated. Among nickel-sensitive individuals, a definite dose-response dependency was seen, following oral exposure to nickel. 7 of 10 nickel-sensitive individuals had cutaneous reactions to oral exposure to 4.0 mg nickel, an amount approximately 10 times greater than the estimated normal daily dietary intake of nickel. 4 of 10 nickel-sensitive individuals had cutaneous reactions to 1.0 mg nickel, a dose which is close to the estimated maximum amount of nickel contained in the daily diet. 4 of 10 nickel-sensitive individuals reacted to 0.3 mg nickel or to the amount equivalent to that contained in a normal daily diet, and 1 of 10 reacted to a placebo. None of the 20 healthy controls had cutaneous reactions to 4.0 mg nickel or to a placebo. Prior to oral exposure, there was no measurable difference in the amount of nickel in the urine or serum of nickel-sensitive persons and healthy controls. Following the oral challenge, the nickel content in the urine and serum of both nickel-sensitive and healthy control individuals was directly related to the dose of nickel ingested.     

A STUDY OF METHODS USED FOR DISINFECTION OF ANAESTHETIC EQUIPMENT BETWEEN TWO SURGICAL OPERATIONS AT A LARGE TEACHING HOSPITAL

A prospective study on the growth of bacteria on certain commonly used anaesthetic equipment was undertaken in a large teaching hospital with a view to assess the effectiveness of disinfection/sterilization procedures. Samples for microbiological assessment were drawn by the worker using standardised procedures and tested in the laboratory by a microbiologist, blinded to the type of sample. Criteria for growth positivity was taken as > 25 colony forming units. A total of 90 observations were taken. 30 each for ’before use’, ’after use’ and ’after disinfection’. Overall 54.6% of the equipment showed growth “before use” with maximum growth being seen in Suction catheters (66.6%) and Guedal airways (60.0%). On the other hand, the proportion of equipment showing growth “after use” was quite high (84.6%), with suction catheters and endotracheal tubes showing 90.0% growth each. There was significant difference as regards “before” and “after” use growth on Endotracheal tubes, Guedel airways and Face masks (p < 0.05). Analysis of growth “after” disinfection” revealed that the probability of growth remains as high as 70% in suction catheters (95% CI=54% to 86%) and 60% in laryngoscopes (95% CI=43% to 78%). The study revealed gross inadequacies in methods of disinfection being followed at present.KEY WORDS: Anaesthetic equipment, Disinfection     

Diagnostic imaging of human neuroblastoma with radiolabeled antibody

In a previous study, the authors showed that iodine-131 labeled monoclonal antibody (Mab 3F8) could be used to image human neuroblastoma xenografts in mice with excellent tumor-to-tissue ratios. In this study they report their experience with six patients scanned with radiolabeled 3F8. There was strong accumulation of the labeled antibody in viable tumor, but no significant uptake was noted in normal brain, liver, spleen, or adrenal glands. Tumor-to-nontumor activity ratios varied but were approximately 10:1-20:1. This ratio yields good contrast for visualization. Time-activity curves show that radioactivity levels in normal tissue have a half-time of about 40 hours, whereas tumor tissues show a half-time of about 60 hours. Significant gastric secretion of free iodine demonstrated that the Mab was being deiodinated. Calculated radiation doses indicate that tumors receive at least ten times the dose to other tissues. The results indicate that Mab 3F8 has clinical potential for both imaging and therapy of human neuroblastomas.