Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were evaluated. FGF-2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg/ml vs. 1.58 pg/ml, P < < < <0.0001). The 25 cases were all active multiple myeloma, and none of the non-active myeloma and MGUS patients showed a high FGF-2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P < < < <0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non-active myeloma and five MGUS. Elevation of FGF-2 level was associated with β β β β2-microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence-Jones type myelomas, including four clinically active cases, revealed a high plasma FGF-2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF-2 levels were significantly decreased after chemotherapy. FGF-2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF-2 level. We conclude that plasma concentration of FGF-2 can be a useful indicator of disease activity.

Recent reports showed that thalidomide has anti-angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty-four evaluable patients (42%) showed more than 25% reduction of M-protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2-4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide ( ≥ ≥ ≥ ≥2.0 µ µ µ µg/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near-normal ranges in responders but were still high in most non-responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P = = = =0.025), but not in non-responders (P = = = =0.37). Reduction of plasma VEGF level might be an important indicator for anti-myeloma effect of thalidomide.

The last UK Haemophilia Centre Doctors' Organization guidelines on the diagnosis of inhibitors (Hay et al, 2000) recommended regular screening for antibodies against factor VIII or factor IX in patients with haemophilia. It was stated that screening is normally conducted using an activated partial thromboplastin time (APTT) based or Bethesda method. An APTT-based method described by Ewing and Kasper (1982) was referenced with the instruction that each laboratory must standardize this test independently and determine what they consider an abnormal result. We do not know of a single haemophilia centre in the UK that uses this method. Many use only Bethesda assay. We describe a screening method that is both simpler and more sensitive than the Bethesda assay, which we have used for several years in the Oxford Haemophilia Centre.A total volume of 0AE4 ml test plasma (or factor-deficient control plasma) is mixed with 0AE1 ml of 5 u/ml of factor concentrate (final concentration 1 u/ml). The mixture is incubated at 37°C for 1 h for haemophilia A patients and 10 min for haemophilia B patients. A factor assay is then performed on the test and the control sample. If the factor level in the test sample is <90% of that in the control sample, the screen is positive. Two recent cases are described. The first, a 9-month-old boy with severe haemophilia B developed a positive screen after four treatment days. The Bethesda assay (with the Nijmegan modifications) (Verbruggen et al, 1995) was <0AE3 Bethesda units (BU)/ml (i.e. below the lower limit of detection) over the next 34 d, during which treatment with factor IX continued. Thirty-six days after the positive screening test he had an anaphylactic reaction to his twelfth dose of factor IX and the Bethesda assay that day was positive for the first time at 1AE6 BU/ml.The second case was an 11-year-old boy with severe haemophilia A and long-standing inhibitors who was treated with rituximab. His antibody disappeared for 7 months, at which time the inhibitor screen became positive. He continued on prophylaxis. The Bethesda assay became positive 3 months later (0AE5 BU/ml) and over these 3 months the half-life declined from 5AE4 to 2AE4 h.In these and many other cases this screening test has proven to be more sensitive than a Bethesda assay. It is considerably simpler and quicker to perform and we recommend it to busy haemophilia centres.

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A 74-year-old