854

four (4, 7, 8, and over 16 months), and stable in four (5, 6, 12, and over 20 months). We found leucopenia grade III in fifteen and grade IV in fourteen of forty treatment cycles. Unfortunately, we had to close the study prematurely because of side-effects: implantation of the venous access port resulted in axillary vein thrombosis in four patients (two of whom had pulmonary embolism), demonstrated by a perfusion lung scan; the third patient died suddenly of unknown cause. Two patients had received radiotherapy to this area previously. A clinical syndrome of peripheral vasculitis with cyanotic painful extremities without clotting abnormalities or signs of diffuse intravascular coagulation developed in one patient, but resolved spontaneously after mitozantrone treatment was ended. Despite the short treatment time, four patients are still alive and three remain in remission at 16, 19, and 20 months, respectively, after the start of treatment. These findings are an improvement on the maximum progression-free survival of 50 weeks in responding patients in Harris and colleagues’ study, despite the unfavourable disease sites (liver in one, pleura in one, pulmonary lymphangitis in one). Treatment of short duration may indeed be effective over longer periods, although continuous exposure to the cytostatic drug may offer a therapeutic advantage, being better tolerated, and may be even more effective than bolus therapy.

Department of Medical Oncology, University of Groningen, 9713 EZ Groningen, Netherlands

N. H. MULDER P. H. B. WILLEMSE E. G. E. DE VRIES A. G. NANNINGA D. TH. SLEIJFER

evidence for cosecretion of IAPP and insulin. Reduction of p-cell function and suppression of insulin release in IDDM II, or near complete damage of the endocrine pancreas in DM I, seems to be reflected by reduced or even absent plasma IAPP. Van Jaarsveld and colleagues do not provide data on the sensitivity of their assay system. In our hands, and according to the manufacturer, the lower limit of the linear range of the RIA system is about 10 pg per vial. Therefore the lowest concentration of detectable IAPP-irm would be 40 pg/ml if 05 ml of plasma is used and duplicate measurements are done. If too small an amount of plasma is used the test will be inaccurate, which might account for the high plasma-IAPP concentrations as well as the failure to detect differences between the groups. Our data provide further evidence for cosecretion of insulin and IAPP, and support the idea that DM II might be partly the result of a dysregulation of the physiologically sensitive cosecretion of insulin with its agonist IAPP. University Medical Clinic II, and Ludwig Boltzmann Institute for Clinical Endocrinology, A-1090 Vienna, Austria

1. Westermark

P, Wernstedt C, Wilander E, Hayden DW, O’Bnen TD, Johnson KH. Amyloid fibrils m human insulinoma and islets of Langerhans of the diabetic cat are denved from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA 1987; 84: 3881-85.

2.

3. 1. Greidanus

J, de Vries EGE, Mulder NH, et al. A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone. J Clin Oncol 1989; 7: 790-97.

Reduced

islet-amyloid polypeptide in insulin-dependent diabetes mellitus

SIR,-Dr Van Jaarsveld and colleagues (Jan 6, p 60) report islet-amyloid polypeptide (IAPP) concentrations in human plasma. IAPP has been isolated from human insulinoma tissue1 as well as from pancreas of type 2 diabetic patients.2 IAPP induces insulinresistance.3-5 By its deposition as pancreatic amyloid it destroys the p-cells. IAPP is being investigated as one of the factors in the pathophysiology of diabetes mellitus type 2.6 Our group has also established an IAPP radioimmunoassay (RIA). RIA components are identical to those used by Van Jaarsveld et al (Peninsula, Belmont, CA, USA). We extracted IAPP immunoreactive material (IAPP-irm) from EDTA-plasma (usually 5 ml) by ’Sep-Pak C18’ cartridges (Waters/Millipore, Milford, MA, USA). IAPP-irm is desorbed by a solution containing methanol/tri-fluoroacetic acid/water in the volume ratio of 90/0-5/ 9-5. Vacuum-concentration (’Speed-Vac’, Savant Instruments) yields dry plasma-extracts. These finally are reconstituted in phosphate RIA buffer and IAPP-irm is measured by conventional RIA (second antibody from Sorin/Biomedica, Saluggia, Italy). The linear range of the RIA is 10-100 pg per vial, and within and between run precisions are 10% and 15%, respectively. If 5 ml of plasma is used, the detection limit of the assay is 2-5 pg/ml. We found the following fasting plasma levels of IAPP-irm in healthy controls and in patients with type 2 diabetes (NIDDM II, oral antidiabetic drugs; IDDM II, receiving insulin) and type 1 diabetes

(DM1):

Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB. Purification and characterisation of a peptide from amyloid polypeptide of type 2 diabetic patients. Proc Natl Acad Sci USA 1987; 84: 8628-32. Leighton B, Garth JS, Cooper JS. Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 1988; 335:

632-35. 4.

Cooper GJ, Leighton B, Dimitriadis, GD, et al. Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen

metabolism in skeletal muscle. Proc Natl Acad Sci USA 1988; 85: 7763-66. Johnson KH, O’Bnen TD, Jordan K, Westermark P Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAAP) immunoreactivity in pancreatic beta cells. Am J Pathol 1989; 135: 245-50. 6. Johnson KH, O’Bnen TD, Betsholtz C, Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 1989; 321: 513-18 7. Nakazato M, Asai J, Kangawa K, Matsukura S, Matsuo H. Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem Biophys Res Commun 1989; 164: 394-99. 5.

Silica and

*Two-tailed Kruskall-Wallis test.

lung

cancer

SIR,-Dr Infante-Rivard and colleagues (Dec 23/30, p 1504) review

retrospective cohort of Quebec males with silicosis receiving compensation. The study was carefully designed and analysed, and is clearly described. However, the implication of a causative role for silica exposure in the development of lung cancer must remain speculative. Infante-Rivard et al acknowledge the selection bias intrinsic in those who had received compensation in 1938-85, on criteria adhered to with varying rigour by compensation boards. Exposure, clinical signs, and radiographic features were the three criteria. One may assume compensated males to have more silicosis (ie, exposure) than non-compensated males. Alternatively, those compensated may have had less pulmonary reserve and were thus more likely to seek and to receive such compensation. Any factor (eg, smoking) affecting pulmonary reserve would move the standardised mortality ratio (SMR) away from the null hypothesis. Smoking may have been a confounder (93% "ever-smokers" in the cohort vs 82% in the standard Quebec male population) but we a

know how much was smoked-critical information, since all lung cancer epidemiological data since Doll and Hill’s landmark paper have shown that SMRs for lung cancer vary directly with amount smoked. In the Vermont granite workers’ study1 almost all the workers had smoked, and Costello and Graham rightly hestitated to link silica exposure independently with an increased risk of lung cancer. In the Quebec cohort no deaths from lung cancer were reported among those who had never smoked. The study lacks the statistical power to detect a stable lung cancer rate among compensated non-smokers; nonetheless we need a better handle on this critical confounder, for only then can we begin to move from a qualified association to an ability to trace causality. can never

IAPP values for controls are in accord with those of Nakazato et al7 The significantly reduced IAPP levels in IDDM II and DM I are

E. HARTTERT. SVOBODA B. LELL M. SCHULLER B. LUDVIK W. WOLOSZCZUK R. PRAGER

Reduced islet-amyloid polypeptide in insulin-dependent diabetes mellitus.

854 four (4, 7, 8, and over 16 months), and stable in four (5, 6, 12, and over 20 months). We found leucopenia grade III in fifteen and grade IV in f...
181KB Sizes 0 Downloads 0 Views