Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study.

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.

Angina intensity is not different in diabetic and non-diabetic patients with acute myocardial infarction.

BACKGROUND: Diabetic patients with acute myocardial infarction (AMI) may have diminished pain or a higher frequency of asymptomatic infarctions. This appears to be a common clinical perception. METHODS: Data from two registries of AMI patients presenting in hospital (MITRA PLUS with 18786 patients; North German Registry, NGR, 1042 patients with detailed symptom interviews) were analyzed concerning symptoms of acute myocardial infarction in patients with diabetes mellitus (DM) and without diabetes (non-DM). RESULTS: DM patients were significantly older and more often female than non-DM. There were no differences in the frequency of pre-infarction angina between DM and non-DM (Mitra Plus). In NGR, severe angina during AMI occurred in 49.8% of DM and 46.3% of non-DM (n. s.). No chest pain was reported in 16.9% of DM and 15.0% of non-DM (n. s.). Extra-thoracic pain, dizziness, nausea, sweating, palpitations, radiation of angina and localization of radiating pain was not different between DM and non-DM patients. Severe dyspnea occurred in 29.5% of DM and 19.5% of non-DM patients (p = 0.003). CONCLUSIONS: Apart from a higher frequency of severe dyspnea in diabetics, there appears to be no difference in the clinical symptoms of AMI patients with and without diabetes mellitus. AMI with little or no angina was also frequently found in non-diabetics. In the hospital, diabetics with suspected AMI do not appear to need a special judgement of symptoms. This could accelerate access of diabetics to standard therapeutic procedures.

[Secondary and primary prophylaxis of gastropathy associated with nonsteroidal antiinflammatory drugs or low-dose-aspirin: a review based on four clinical scenarios]. / Sekundär- und Primärprophylaxe der ASS-/NSAR-Gastropathie: Eine Ubersicht anhand vier klinischer Szenarien.

Based on current references four clinical scenarios were discussed and different management strategies were compared for secondary and primary prophylaxis of ulcer or peptic ulcer bleeding under continuous therapy with non-steroidal antiinflammatory drugs (NSAID) or low-dose-aspirin, for H.pylori-positive and H.pylori-negative patients. Used as secondary prophylaxis eradication alone is insufficient in preventing recurrent peptic ulcer or recurrent ulcer bleeding for H.pylori-positive patients who continue to take unselective NSAIDs. Maintenance therapy with PPIs or switching from nonselective NSAID to COX-2-inhibitors is required after eradication of H.pylori or primary H.pylori-negative patients. Further evaluation is needed of what kind of secondary prophylaxis - maintenance therapy with PPI or switching to COX-2-inhibitor - is more (cost-)effective. It is sufficient to use eradication of H.pylori alone as secondary prophylaxis in preventing recurrent peptic ulcer or recurrent ulcer bleeding for H.pylori-positive patients, who continue to take low-dose-aspirin. Maintenance therapy with PPI is not generally required. However it can be considered for patients with increased risk for gastrointestinal complications (previous history of peptic ulcer, age over 65 years, concomitant use of corticosteroids, anticoagulants or individual NSAID with higher risk for gastrointestinal complications, serious cardiovascular disease). Switching from low-dose-aspirin to clopidogrel is not required. Used as primary prophylaxis in preventing peptic ulcer or ulcer bleeding before starting long-term therapy with NSAIDs, COX-2-inhibitors or unselective NSAIDs concomitant with PPIs are recommended for patients with increased risk for gastrointestinal complications. Patients starting long-term therapy with unselective NSAIDs should be screened for H.pylori and eradicated. There are no valid data supporting screening for H.pylori and eradication for patients starting long-term therapy with low-dose-aspirin. Further studies are needed to evaluate a possible benefit for patients with increased risk for gastrointestinal complications.

[Day-night variability of the prehospital phase of acute myocardial infarct]. / Tag-Nacht-Variabilität der Prähospital-Phase des akuten Myokardinfarktes.

While a circadian rhythm in the onset of acute myocardial infarction (AMI) is well established, little is known about the variability of prehospital delay and decision processes. Seven hundred and thirty-nine consecutive AMI patients (median age 65.3 years; 30.2% women) with a median decision time of 60 min and a total prehospital delay of 180 min were studied. In 30.9% of patients onset of AMI symptoms was at night (10.00 p.m.-06.00 a.m.). At night patient decision time was significantly longer than during daytime (120 vs 45 min, difference 75 min; p < 0.001), total prehospital delay was prolonged accordingly (240 vs 170 min, difference 70 min; p < 0.001). The relative risk (RR; 95% confidence interval, CI) for a late decision (> 1 h) to seek medical care at night was significantly increased in females (RR 1.96; CI 1.07-3.61, p = 0.028), non-smokers (RR 2.49; CI 1.42-4.39, p = 0.001) and patients with radiation of anginal pain (RR 2.34; CI 1.32-4.15; p = 0.003). Of all patients with a late decision to seek medical care at night, 95.6% belonged to one of these groups. These variables were not significant for early or late decisions during daytime. Decision processes of AMI patients may be different during daytime and at night. In conclusion, in AMI patients, decision time to seek medical help is prolonged at night. Simple clinical variables (female sex, non-smokers, radiation of anginal pain) identify patients at high risk for a late decision at night. This information should be included into public and individualized education campaigns.

Emotional attitudes toward symptoms and inadequate coping strategies are major determinants of patient delay in acute myocardial infarction.

BACKGROUND: Early reperfusion treatment in acute myocardial infarction (AMI) preserves ventricular function and saves lives. After onset of AMI symptoms, patients often delay for hours until the decision to seek medical help. AIM: Of the MI-heart (Myocardial Infarction--HElp seeking And ReacTions) study was to identify factors determining patient decision delay. METHODS: 739 consecutive patients with confirmed AMI (median age 65.3 years, 30.2% females) were studied after transfer from the intensive care unit. A standardized interview covered AMI symptoms, attitudes toward symptoms, coping strategies, and clinical and sociodemographic variables. RESULTS: Of patients, 93.3% knew an AMI could be deadly. 43.9% of the patients who suspected an AMI, and knew it could be deadly, decided late (> 1 hour) to seek medical help. In univariate analyses, attitudes toward symptoms and coping strategies had the highest impact on a late decision. Stepwise logistic regression identified the following independent contributors to a late decision to seek medical help (relative risk, 95% confidence interval): wanting to wait and see (3.53; 2.32-5.39), not taking symptoms seriously (2.47; 1.64-3.72), not wanting to bother anybody (2.14; 1.29-3.57), symptoms improving at first (2.33; 1.52-3.56), asking others for advice (0.46; 0.30-0.71), taking pain medication (2.01; 1.01-4.03), age > 65 years (1.69; 1.17-2.44), very strong intensity of angina (0.60; 0.42-0.87). CONCLUSIONS: Emotional attitudes to AMI symptoms and inadequate coping strategies are the major determinants of patient decision delay. They should be considered as a key factor in patient and public education. Modification of these emotional factors might best be achieved by an individualized approach.

[Bradycardia despite hyperthyroidism]. / Bradykardie trotz Hyperthyreose.

Hyperthyroidism is usually associated with tachycardia, hypothyroidism with bradycardia. After observing clinically inapparent hyperthyroidism in patients requiring pacemaker implantation, we studied the occurrence of hyperthyroidism in patients receiving a first permanent pacemaker. Of 237 patients (age 71.4 +/- 8.9 years; 54.9% females), 16 (6.75%) had subclinical (TSH < 0.1 mE/l and fT3 < or = 9.0 pmol/l) and 4 (1.69%) overt hyperthyroidism (TSH < 0.1 mE/l and fT3 > 9.0 pmol/l). Prevalence of hyperthyroidism was similar to that in the general population. Compared to euthyroid patients, in the patients with subclinical or overt hyperthyroidism there were significantly more females (n = 16) than males (n = 4; p = 0.018). Hyperthyroid patients were older (75.0 +/- 9.6 vs. 70.7 +/- 8.9 years; p = 0.015). At follow-up, all patients had a relevant proportion of pacemacer-induced beats. Clinical signs of hyperthyroidism or cardiac symptoms were not different between groups. In conclusion, bradycardia does not exclude the presence of hyperthyroidism. Temporary pacing is recommended in thyreotoxicosis with bradycardia. In contrast, primary implantation of a permanent pacemaker appears to be adequate in patients with bradycardia, cardiovascular disease and an additional diagnosis of hyperthyroidism.

Out-of-hospital cardiac arrest in north-east Germany: increased resuscitation efforts and improved survival.

In the years after 1989 major political and socioeconomic changes have taken place in East Germany. In parallel, emergency medical services (EMS) were restructured according to western standards. In Stralsund the EMS was restructured from a single to a two tier system with implementation of a second ambulance base in 1990. The number of household telephone extensions more than doubled. To analyze the effects of these changes, patients receiving advanced life support (ALS) for out-of-hospital cardiac arrest of cardiac origin (OHCA) between 1984 and 1988, and from 1991 to 1997 were studied. Adjusted per 100,000 inhabitants, the number of OHCA patients receiving ALS increased from 11 per year before 1989 to 52 per year after 1990 (P < 0.01). Survival without relevant neurologic defects was achieved in 3.7% (2/53) of patients before 1989 and in 8.1% (22/273) after 1990. Response time of the ALS unit shortened from 11.0 +/- 1.4 to 9.0 +/- 0.4 min (n.s.), while response time of any EMS shortened from 11.0 +/- 1.4 to 6.1 +/- 0.3 min (P < 0.005). Adjusted for observation period and population served, there was a 10-fold increase in the number of resuscitations attempted at home and an 8-fold increase in the absolute number of OHCA survivors without relevant neurological defects. In parallel to socioeconomic changes, the restructuring of the EMS in Stralsund and the rapid expansion of the telephone network led to a significant increase in the number of patients successfully resuscitated from OHCA. If the present results can be transferred to other former socialist countries of East and Middle Europe, they may have important implications for the EMS in these regions.

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML).

Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged 60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged

Metastatic workup of patients with prostate cancer employing alkaline phosphatase and skeletal alkaline phosphatase.

PURPOSE: To compare the efficacy of two tests, alkaline phosphatase (AP) and skeletal alkaline phosphatase (SAP) as staging markers to discriminate patients with cancer of the prostate (CaP) with bone metastases (M+) from those without bone metastases (Mo). MATERIALS AND METHODS: Patients with previously untreated CaP were entered in the retrospective analysis. Serum concentrations of AP (n = 215) and SAP (n = 73) were available. After staging the patients could be divided into 2 groups: Group I: patients with CaP and bone metastases (cT2-4 NxMoss AP: n = 40; SAP: n = 21) Group II: patients with CaP without bone metastases (cT3-4 Nx Mo; pT1-3 No Mo; AP: n = 175; SAP: n = 52). RESULTS: None of the Mo patients but 71% of the M+ patients exhibited a SAP value above the reference range (< 19 ng/ml). This difference is statistically significant (p < 0.001) and resulted in a sensitivity and specificity of 71% and 100%, respectively. The Youden-index is 0.7. In contrast 7% of the Mo patients and only 13% of the M+ patients exhibited a AP value above the reference range (< 170 U/l). This difference is statistically not significant (p = 0.71) and resulted in a sensitivity and specificity of 13% and 93%, respectively. The Youden-index is 0.06. CONCLUSION: SAP could become a useful marker in the evaluation of patients with newly diagnosed CaP as it provides more information than AP concerning the skeletal status of these patients.

Regulation of beta2-microglobulin expression in different human cell lines by proinflammatory cytokines.

BACKGROUND: Proinflammatory monocytic cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and IL-6 have been incriminated in the pathogenesis of elevated beta2-microglobulin (beta2M) serum concentrations in patients undergoing haemodialysis with so-called bioincompatible dialyser membranes. However, neither the source of the elevated serum beta2M nor the precise role of monocytic cytokines in the expression of the beta2M gene have been elucidated conclusively. The aim of the current study was to evaluate whether monocytic cytokines, and in particular IL-6, are regulators of beta2M gene expression in human hepatoma cells, T-lymphocytes and monocytes. METHODS: HepG2 and HuH7 human hepatoma cells, Jurkat T-cells, monocytic MonoMac6 cells, primary human monocytes and synoviocytes were stimulated with IL-1beta, IL-6, interferon-alpha (IFN-alpha), IFN-gamma or conditioned media from lipopolysaccharide (LPS)-treated monocytes. Expression of beta2M mRNA was analysed by Northern blotting, beta2M protein synthesis was determined by metabolic labelling and immunoprecipitation, and beta2M secretion was measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: In all cell types tested, IFN-gamma and, to a lesser extent, IFN-alpha stimulated gene expression of beta2M resulting in an increased synthesis and secretion of beta2M protein. Neither IL-1beta and IL-6 nor supernatants from LPS-treated monocytes were capable of inducing beta2M gene expression, with the exception of a small increase in HuH7 hepatoma cells upon IL-1beta treatment. CONCLUSIONS: The present study provides evidence that interferons are important regulators of beta2M expression. It also shows that proinflammatory monocytic cytokines do not modulate directly the expression of beta2M in cells of hepatic, monocytic and T-lymphocytic origin. Whether they influence beta2M synthesis and secretion indirectly by modulating interferon synthesis needs to be elucidated.