In patients with multiple myeloma, despite a major reduction of bone pain achieved with chemotherapy, skeletal disease continues to progress. The effects of clodronate, an inhibitor of osteoclastic bone resorption, are evaluated on the natural history of skeletal disease in patients with newly diagnosed multiple myeloma. Within the framework of the VIth MRC Multiple Myeloma Trial, 536 patients (218 women, 318 men) with recently diagnosed multiple myeloma were randomized to receive either clodronate 1600 mg daily (n=264) or an outwardly identical placebo (n=272) in addition to chemotherapy. Treatment with clodronate was associated with a 50% decrease in the proportion of patients with severe hypercalcaemia (5.1% v 10.1%, P=0.06) and a similar reduction in reported non-vertebral fractures (6.8% v 13.2%, P=0.04). Fewer patients receiving clodronate sustained vertebral fractures after entry to the trial (38% v 55%, P=0.01) and patients also lost less height over 3 years compared to those receiving placebo (2.0 v 3.4 cm, P=0.01). Biochemical indices of bone turnover were significantly lower in patients receiving concomitant clodronate, both at plateau and at disease relapse. The frequencies of back pain and poor performance status were significantly lower at 24 months in clodronate than in placebo-treated patients (10.9% v 19.9%, P=0.05, and 18.3% v 30.5% P=0.03 respectively.) There was no statistically significant difference in survival between the clodronate and placebo treated patients. The study indicates that long-term oral clodronate slows the progression of skeletal disease in multiple myeloma and decreases the associated morbidity. Patients without overt skeletal disease at diagnosis were also found to benefit from clodronate, indicating that this treatment should be initiated as early in the course of the disease as possible.
Summary. Differentiation therapy using retinoic acids (RAs) or 1a25-dihydroxyvitamin D 3 (D 3 ) is an attractive alternative to chemotherapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). However, with the exception of RA therapy for acute promyelocytic leukaemia (APL), RAs and D 3 are not potent enough at doses that can be tolerated by patients. We demonstrate that clofibric acid (CA) enhances the response of HL60 cells to all-trans RA and D 3 . Our findings and those of others in the field lead us to suggest that combination therapy using all-trans RA and CA should be considered as potential therapy for AML and MDS.
A fter referring to the evidence of the occurrence of a Glacial Epoch, and to the various hypotheses which have been proposed to account for it, the author brought forward the following considerations:— Of the three principal movements of the earth, namely its daily rotation on its axis, its revolution round the sun, and the slow conical movement of its axis of rotation round the poles of the ecliptic, the third is, in the author’s opinion, the cause of glacial epochs. The angular distance of the pole of the ecliptic and the pole of the heavens is at all times the exact measure of the obliquity of the ecliptic, or the extent of the Arctic circle upon the earth. There is evidence that during the last 2000 years these two poles have gradually decreased their angular distance, so that, while the pole of the heavens moves round some curve at the rate of about 1° in seventy-two years, it approaches the pole of the ecliptic at a variable rate, at present about 46″ in a century. The author had calculated from the recorded positions of the pole of the heavens during the last 2000 years, the curve traced by this pole with relation to the pole of the ecliptic. He found it to be a circle, the centre of which is 6° from the pole of the ecliptic, and 29° 25′ 4.7″ from that of the heavens. Taking this curve as a guide, the author finds that 2000 years ago the
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