Human recombinant insulin and amyloidosis: an unexpected association.

A 48-year-old patient with diabetes mellitus was treated with human (recombinant) insulin. He developed cutaneous amyloidosis twice at different locations where subcutaneous insulin had been injected. There were no signs of systemic amyloidosis. Additional pathological-anatomical investigations demonstrated insulin in one (the most recent) amyloid tumour. A limited number of similar cases have been reported in the literature, although mostly associated with porcine insulin. Cutaneous amyloidosis may be associated with local injections of human (recombinant) insulin. One should therefore also consider this diagnosis when finding tumours at sites where insulin has been injected.

Transanal endoscopic microsurgery versus total mesorectal excision of T1 rectal adenocarcinomas with curative intention.

PURPOSE: After total mesorectal excision (TME) for rectal cancer, pathology is standardized with margin status as a predictor for recurrence. This has yet to be implemented after transanal endoscopic microsurgery (TEM) and was investigated prospectively for T1 rectal adenocarcinomas. PATIENTS AND METHODS: Eighty patients after TEM were compared to 75 patients after TME. The study protocol included standardized pathology. TEM patients were eligible when excision margins were negative. RESULTS: TEM was safer than TME as reflected by operating time, blood loss, hospital stay, morbidity, re-operation rate and stoma formation (all P<0.001). Mortality after TEM was 0% and after TME 4%. At 5 years after TEM and TME, both overall survival (TEM 75% versus TME 77%, P=0.9) and cancer-specific survival (TEM 90% versus TME 87%, P=0.5) were comparable. Local recurrence rate after TEM was 24% and after TME 0% (HR 79.266, 95% CI, 1.208 to 5202, P<0.0001). CONCLUSION: For T1 rectal adenocarcinomas TEM is much saver than TME and survival is comparable. After TEM local recurrence rate is substantial, despite negative excision margins.

Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy.

In view of the similarity in chemical structure of the available 5HT(3)-receptor antagonists it is assumed, whilst these agents all act at the same receptor, that failure to one agent would predict subsequent failure to all 5HT(3)-receptor antagonists. We conducted a randomized double blind trial of granisetron 3 mg plus dexamethasone 10 mg versus continued treatment with ondansetron 8 mg plus dexamethasone 10 mg in patients with protection failure on ondansetron 8 mg plus dexamethasone 10 mg during the first 24 hours following highly emetogenic chemotherapy. Of 40 eligible patients, 21 received ondansetron + dexamethasone and 19 received granisetron + dexamethasone. We found a significant benefit from crossing-over to granisetron after failure on ondansetron. Of the 19 patients who crossed over to granisetron, 9 patients obtained complete protection, whereas this was observed in 1 of the 21 patients continuing ondansetron, P = 0.005. These results indicate that there is no complete cross-resistance between 5HT(3)-receptor antagonists, and that patients who have acute protection failure on one 5HT(3)-receptor antagonist should be offered cross-over to another 5HT(3)-receptor antagonist.

The significance of venography in the management of patients with clinically suspected pulmonary embolism.

The accurate diagnosis of pulmonary embolism causes many problems. Clinical signs are non-specific, and ventilation-perfusion lung scanning has high sensitivity but variable specificity. In more than 90% of cases a pulmonary embolus is derived from deep venous thrombosis in the lower extremities. We have performed a prospective study to evaluate venography in the management of patients with suspected pulmonary embolism. A total of 169 patients were included in the study, and a ventilation-perfusion scan was performed in all cases. Forty-four (26%) patients had a normal scan and treatment was not given (group A). The other 125 (74%) patients, who had an abnormal scan, underwent bilateral venography. Venous thrombosis was demonstrated in 63 patients, and they were treated with oral anticoagulants for 3 months (group B). The remaining 62 patients, who showed no venous thrombosis, did not receive anticoagulant therapy (group C). During follow-up, 1 patient in group A, 3 patients in group B and 1 patient in group C developed a new deep venous thrombosis. One patient in group B suffered a pulmonary embolus. It is concluded that venography of the lower extremities can be of additional value in the management of patients with pulmonary embolism when the lung scan does not provide sufficient information.

Is quantitative determination of fibrin(ogen) degradation products and thrombin-antithrombin III complexes useful to diagnose deep venous thrombosis in outpatients?

We studied the diagnostic value of recently introduced ELISA's for the determination of thrombin-antithrombin III (TAT) complexes, fibrin degradation products (FbDP), fibrinogen degradation products (FgDP) and total degradation products (TDP) for deep venous thrombosis (DVT) in plasma of 239 consecutive outpatients, suspected for DVT by their family doctor. DVT was confirmed by impedance plethysmography in 60 patients. Using the 95th percentile range of 42 healthy volunteers the sensitivity for the detection of DVT was: 37% for TAT, 95% for TDP, 92% for FbDP and 90% for FgDP. Specificity was: 88% for TAT, 16% for TDP, 20% for FbDP and 25% for FgDP. We conclude that these assays are of little value in the diagnosis of DVT in outpatients.

The value of adding thermographic leg scanning to impedance plethysmography in the detection of deep vein thrombosis.

The clinical value of adding thermographic leg scanning to impedance plethysmography was evaluated and compared in 52 patients with clinically suspected deep venous thrombosis. Both tests were performed on the day of referral and phlebography within 72 hours. The sensitivity of thermography was 83%, the specificity 41% and the accuracy 61%. In comparison IPG had a sensitivity of 83%, a specificity of 96% and an accuracy of 90% The combination of thermography and IPG showed a sensitivity of 92%, a specificity of 41% and an accuracy of 65%. It is concluded that the addition of thermography to IPG is of no clinical value.

An evaluation of suloctidil in the prevention of deep vein thrombosis in neurosurgical patients.

Suloctidil (200 mg t.i.d.) was compared with placebo in a randomized, double-blind trial to assess its value in preventing deep venous thrombosis (DVT) in high-risk neurosurgical patients, comprising 136 patients with brain or spinal tumour, head or spinal injury, or subarachnoid or intracranial hemorrhage. 125I fibrinogen leg scanning and impedance plethysmography were performed for up to 14 days to detect DVT. The two groups were also evenly balanced for DVT risk factors. Seventeen of 68 patients (25%) (95% confidence interval, 15-35%) treated with suloctidil and 12 of 68 patients (21%) (95% confidence interval, 11-32%) treated with placebo developed deep venous thrombosis. This observed difference in outcomes is not statistically significant (X2 = 1.096; p = 0.30). The estimated 95% confidence interval for the true difference in the incidence of DVT between suloctidil-treated and placebo-treated patients ranges from an 11% benefit in favour of suloctidil to an 18% benefit in favour of placebo. Major deep vein thrombosis occurred in two patients on suloctidil and three patients in the placebo group; there were no fatal pulmonary emboli during the 14-day study period, during which time four patients in each group died of non-thromboembolic complications. There was no observed difference in hemorrhagic complications. Long-term outcomes at three-months follow-up were similar between the two treatment groups. It is concluded that there is no real evidence that suloctidil (200 mg t.i.d.) is an effective regimen for the prevention of DVT in high-risk neurosurgical patients.

The effect of diabetes regulation on platelet release, fibrinolysis and coagulation tests, before and after stimulation with DDAVP.

In this longitudinal study we measured beta-TG, PF4, fibrinolytic activity (extrinsic and euglobulin fraction), fibrinogen, FVIII RAg and FVIII Rcof before and after i.v. DDAVP (FPA was only measured before DDAVP) in 20 patients with diabetes mellitus. These parameters were measured on three occasions: phase I: during disregulation, phase II: after three weeks of strict control, phase III: after nine weeks of good control. Twenty-two healthy volunteers served as normal controls. No significant differences related to metabolic control were found for beta-TG, PF4, FPA and fibrinogen. There was no change after i.v. DDAVP administration. Fibrinolytic activity showed a significant increase after i.v. DDAVP. Baseline values and post-DDAVP increase were not significantly different from our normal controls. FVIII RAg and FVIII Rcof were both significantly elevated in diabetes mellitus. Both increased significantly after DDAVP. The FVIII RAg release (delta FVIII RAg) was significantly less in the diabetics. Fibrinolytic activity, FVIII RAg and FVIII Rcof are independent of the degree of metabolic control in patients with diabetes.

Exercise capacity with transdermal nitroglycerin in patients with stable angina pectoris.

Transdermally delivered nitroglycerin (TTS-NTG) through a rate-controlling membrane yields stable blood levels for 24 h. We studied the effect of TTS-NTG (25 mg per 10 cm2) on exercise induced angina in 10 patients with stable angina pectoris, all in NYHA class III, who were not under treatment with other cardiac drugs. In a pre-study exercise test, all patients had angina pectoris and more than one mm ST depression. The study was placebo controlled and double blind with a randomized cross-over. Exercise tests were carried out on a treadmill according to the Bruce-protocol, 12 to 16 h after administration of TTS-NTG or of an identical placebo. After a 48 h wash-out period, the procedure was repeated after application of a plaster with the alternative content. A significant improvement was seen on TTS nitroglycerin compared with placebo in the total duration of exercise (7.2 +/- 3.6 min (mean +/- SD) vs 6.2 +/- 3.8 min; P less than 0.002). In 7 patients, the time to onset of angina was extended by TTS nitroglycerin. Maximal ST depression (lead V4 and V6) was significantly lower on TTS nitroglycerin (1.85 +/- 1 mm) compared with placebo (2.2 +/- 1 mm; P less than 0.05). It is concluded that 12 to 16 h after administration, transdermally delivered nitroglycerin improves exercise capacity and reduces maximal ST depression in patients with stable angina.

Platelet tests and antiplatelet drugs in coronary artery disease.

This study was designed to clarify discrepancies in the literature concerning platelet survival time and beta-thromboglobulin (beta TG) levels in patients with coronary artery disease (CAD) and the effect of platelet-suppressant drugs on these tests. Platelet survival time and plasma beta TG levels were determined in 48 patients with angiographically documented CAD. The effect of sulfinpyrazone or aspirin/dipyridamole on these measurements was investigated in a double-blind, crossover trial that included a placebo phase. In patients with CAD, the mean plasma beta TG concentration was significantly elevated, but the mean platelet survival time was not significantly different from that in controls. Treatment with sulfinpyrazone or aspirin/dipyridamole did not produce changes in platelet survival time or plasma beta TG concentration that were significantly different from the values during the placebo phase. This study demonstrates that compared with the spontaneous variation in platelet survival time or beta TG concentration, there was no measureable effect of sulfinpyrazone or aspirin/dipyridamole on the results of the tests.

Home-diagnosis of deep venous thrombosis with impedance plethysmography.

In order to assess the value of I.P.G. for the diagnosis of D.V.T. in general practice, an I.P.G. was carried out by a skilled technician in 255 consecutive patients with suspected D.V.T. at home. Ascending venography was carried out in 185 of these patients. In addition, blood for assay of AT III, platelet count, fibrinogen, a2-antiplasmin, ethanol gelation test and spontaneous platelet aggregation was collected at the time the I.P.G. was performed. In 61 patients (33%) venography showed the presence of D.V.T., and was negative in the remaining 124 patients. I.P.G. was positive in 51 of the 61 patients with D.V.T., a sensitivity of 84%. I.P.G. was normal in 115 of the 124 patients with a negative venogram, a specificity of 93%. The sensitivity of the I.P.G. for proximal vein thrombosis was 92% and for calf vein thrombosis 68%. Mean a2-antiplasmin concentration was significant (p less than 0.05) lower (101 +/- 15%, mean +/- SD) in patients with D.V.T. compared with patients with a normal venogram (107 +/- 11%, mean +/- SD). No differences between the two groups were observed in the other coagulation parameters assayed, and none was of diagnostic value, either alone or in combination with I.P.G. This study shows that I.P.G. is of potential value for the home diagnosis of D.V.T., in particular proximal vein thrombosis. This is potentially clinically useful, because these thrombi are thought to carry a high risk for pulmonary embolism.

The incidence of deep venous thrombosis in patients with an acute myocardial infarction treated with acenocoumarol or indobufen.

In a randomized double blind clinical trial, we compared indobufen, an antiplatelet drug, with acenocoumarol for the prevention of deep venous thrombosis (D.V.T.) in patients with acute myocardial infarction. Therapy was started on admission and continued for 10 days. All patients were screened daily with impedance plethysmography (I.P.G.) and 125I-fibrinogen leg scanning. Diagnosis of D.V.T. was made when either one or both tests became positive. 74 patients were randomized to treatment with indobufen (200 mg b.i.d.) and 76 patients to acenocoumarol (controlled by thrombotest). The incidence of venous thrombosis in patients with indobufen was 11% and in those treated with acenocoumarol 9%. Major bleeding was observed in 2 patients treated with acenocoumarol. In the indobufen group, no bleeding complications or other serious side-effects were observed. The majority of patients developed thrombosis after the first week of admission. For patients with and without thrombosis, there was no significant difference between the two treatment groups concerning the age, the coronary prognostic index, the maximum C.P.K. value, mobility, incidence of congestive heart failure and the site or extent of the infarct. In this study no clinical or laboratory (fibrinogen, platelet count and anti-thrombin III) parameter, either alone or in combination, was of predictive value for the development of D.V.T. It can be concluded that indobufen appears to be as good as acenocoumarol for the prevention of D.V.T. in patients with acute myocardial infarction. Because it is safe and easy to administer, indobufen seems to be preferable. Prophylaxis is required for at least 10 days.

Platelet release and thromboxane synthesis in symptomatic coronary artery disease.

The incidence and significance of platelet activation in myocardial ischemia was evaluated by serial measurement of plasma thromboxane B2 (TXB2) and beta thromboglobulin (beta TG) in plasma and urine in 98 patients admitted to a coronary care unit with chest pain. All measurements were normal in the 26 patients with noncardiac chest pain. Mean plasma TXB2 and beta TG concentration, but not urine beta TG, were elevated in the 25 patients with myocardial infarction and the 47 patients with angina. The beta TG levels remained normal in 61% of the patients with angina or infarction. The TXB2 levels were significantly higher in patients with recurrent episodes of angina at rest than in those without ischemic episodes after admission. There was a weak correlation between plasma TXB2 and plasma beta TG (r = 0.20, p less than 0.01) and between plasma and urine beta TG (r = 0.31, p less than 0.01). Results indicate that platelets are frequently activated with myocardial ischemia or infarction. However, the measurement of beta TG and TXB2 is of limited value in detecting or differentiating myocardial ischemia from infarction and therefore lacks clinical value in the management of patients with ischemic heart disease.

Platelet consumption in cardiovascular disease.

Many tests have been devised to investigate the role of platelets in arterial or venous thromboembolism. The mechanisms of platelet reactivity that the tests have measured have been variable and the early studies have been of little value in determining the contribution of platelet consumption in thromboembolic diseases. More recently, tests of in vivo platelet release and of platelet survival and turnover have been introduced and thought to be of great potential in the investigation of thromboembolic disorders. However, the data published thus far using more tests are far from conclusive that platelet activation and consumption occurs in thromboembolic disorders associated with arteriosclerosis. It may be that they are neither sensitive nor specific enough to detect minor changes in platelet activation. There is, however, some consistency that in conditions involving the larger vessels, prosthetic surfaces, or in association with active and recurrent venous thromboembolism, platelet release and platelet consumption measured by platelet survival time may occur. In particular, the abnormal results are consistently found in acute and recurrent venous thromboembolism, cardiac valve replacement with the older prosthetic devices, and arteriosclerosis of the larger arteries with clinical episodes of thromboembolism. However, in coronary artery disease, cerebrovascular disease, and peripheral vascular disease, the data are inconclusive, probably because the tests lack sensitivity. In addition, the value of the tests in the management of patients with thromboembolic disorders appears to be limited.

Plasma betathromboglobulin and serum fragment E in acute partial stroke.

Plasma betathromboglobulin (BTG) and serum fragment E (FgE) were measured serially by radioimmunoassay for 7 d in 67 patients admitted with acute partial stroke. Twelve patients progressed within 7 d of admission. Plasma BTG was not different from normal in patients with acute partial stroke and did not increase significantly with stroke progression. Serum FgE was elevated in patients with acute partial stroke compared with normal values, and was significantly higher in patients who progressed compared with those who remained stable. The results indicate that fibrin formation may be more important in the process of stroke progression than activation of platelets.