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.     

Immunologic abnormalities in myelofibrosis with activation of the complement system

Eighteen patients with agnogenic myeloid metaplasia with myelofibrosis were studied for clinical and laboratory evidence of immunologic dysfunction. Clinical findings included the presence of arthritis, vasculitis, and erythema nodosum. Laboratory abnormalities included the presence of circulating immune complexes, antinuclear antibodies, positive direct Coombs tests, elevated latex fixations, and a circulating lupus type anticoagulant. Total hemolytic complement was markedly depressed in four patients. Analysis of complement (C) components C1-C9 and factor B demonstrated significant reduction of only C3 and factor B. By crossed-immunoelectrophoresis, both C3 and factor B, but not C4, were cleaved, indicating that C activation was occurring predominantly via the alternative pathway. The control proteins beta 1H and C3b inactivator were decreased in three of four patients with hypocomplementemia. These data suggest that immunologic mechanisms associated with activation of the complement system play an important role in the disease process of some patients with agnogenic myeloid metaplasia with myelofibrosis.     

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.     

Trends in the use of cytoreductive nephrectomy in the United States

BackgroundTwo randomized trials published in 2001 established CyNx for patients with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era. However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR TKIs. We evaluated the patterns of use of CyNx from 2000 to 2008.Materials and MethodsThe National Cancer Database was queried for patients diagnosed with mRCC. Patients who underwent CyNx were identified and were further categorized by pre-VEGFR versus VEGFR TKI era, race, insurance status, and hospital. For these subcategories, prevalence ratios (PRs) were generated using the proportion of patients with mRCC undergoing CyNx versus those not undergoing CyNx.ResultsOf the 47,417 patients (pts) identified with mRCC, the prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2005 (P < .0001), then decreased 3% each year from 2005 to 2008 (P = .0048), with a significant difference between the eras (0.97 vs. 1.025; P < .0001). Black and Hispanic pts were less likely than Caucasian pts to undergo CyNx. Pts with Medicaid, Medicare, and no insurance were less likely than pts with private insurance to undergo CyNx. Pts diagnosed at community hospitals were significantly less likely than pts at teaching hospitals to undergo CyNx.ConclusionThe use of CyNx has declined in the VEGFR-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the VEGFR-TKI era are awaited to optimize use of this modality and address potential disparities.     

Hematopoietic stem cells mobilization and immune response in tumor-bearing mice

INTRODUCTION: Malignant diseases are known to modulate the number and function of myeloid, erythroid, and lymphoid cells. Since these cells are derived from hematopoietic stem cells (HSC), it is not clear if the observed effects of cancer on such cells are direct or indirect via stem cells. The purpose of this study was to evaluate the effect of breast cancer upon the levels and activity of peripheral blood hematopoietic stem cells. MATERIALS AND METHODS: Four weeks following the establishment of 4T1 breast cancers in BALB/c mice, the animals were killed, blood and spleen harvested, and processed for light density mononuclear cells. Colony forming unit in culture assay was used to determine the activity of HSCs. Flow cytometry was used to determine the levels of lineage negative HSCs expressing c-kit and Sca-1 antigen (Lin c-kitSca-1). Mitogenic, cytotoxic and ELISPOT assays were used to evaluate functional properties of cells. Plasma cytokine levels were determined with ELISA assay. RESULTS: In tumor-bearing mice, there was a 2- and 4-fold increase in the levels and proliferative capacity of HSCs, respectively, compared with controls. Contemporaneously, there was a 13-fold increase in plasma G-CSF in tumor-bearing animals compared with controls (0.225 ng/ml versus 3.0 ng/ml). Furthermore, the number of interferon gamma-secreting cells was significantly increased in tumor-bearing animals. Concurrently, cytotoxic activity of NK cells was significantly increased in tumor-bearing animals as compared with controls (22.4 +/- 10.6 versus 10.3 +/- 2.95; P < 0.05). SUMMARY: These results suggest that (1) breast cancer mobilizes hematopoietic stem cells in mice presumably through G-CSF production, and (2) that such cancer-mobilized stem cells give rise to immune cell lineages which are functionally hyperactive in their cytotoxic activities. Such cells could be expected to have appreciable therapeutic benefit in terms of cancer cell cytotoxic activity when used as part of stem cell transplantation therapy in cancer patients.     

The National Lesbian Family Study: 3. Interviews with mothers of five-year-olds

This third report from a longitudinal study of lesbian families presents data obtained from interviews with mothers of five-year-old children conceived by donor insemination. Results indicated that 87% of the children related well to peers, 18% had experienced homophobia from peers or teachers, and 63% had grandparents who frankly acknowledged their grandchild's lesbian family. Of the original couples, 31% had divorced. Of the remainder, 68% felt that their child was equally bonded to both mothers. Concerns of lesbian families are discussed.     

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