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Background —We conducted a 10-year follow-up of the 11 712 patients with acute myocardial infarction randomized in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 study, the first large trial assessing thrombolytic therapy. Methods and Results —Information on survival at 10 years was obtained for the 93% of all randomized patients through the census offices of their towns of residence. The difference in survival produced by streptokinase and sustained up to 1 year was still significant at 10 years (log-rank test, P =0.02), with the absolute benefit of 19 (95% CI 1 to 37) lives saved per 1000 patients treated. The time dependence of the extent of the benefit was confirmed, as the higher mortality rate reductions found in patients treated earlier were still present at 10 years. In the overall population, most of the benefit was obtained before hospital discharge (RR 0.81, 95% CI 0.72 to 0.90), since no difference in survival between thrombolyzed and control patients discharged alive was found at 10 years (RR 0.98, 95% CI 0.90 to 1.06). However, a slight albeit nonsignificant divergence of the survival curves of patients randomized within the first hour was observed [90 (95% CI 34 to 146) lives saved per 1000 at 10 years versus 72 (95% CI 37 to 107) lives saved at hospital discharge]. Conclusions —The benefits of a single intravenous infusion of 1.5 million units of streptokinase in prolonging survival of patients with acute myocardial infarction is sustained up to 10 years, with a still-evident trend in favor of the patients admitted earlier.

To evaluate the prevalence of type I silent myocardial ischemia and silent myocardial infarction, 4,842 men aged 40 to 59 years, identified in occupational samples in Florence and Rome, and free from major heart disease, severe illnesses and chest pain, underwent a 3-stage diagnostic procedure. The first stage included resting electrocardiogram, hyperventilation test, exercise electrocardiogram and 24-hour Holter electrocardiogram. The subjects who were suspected of having type 1 silent myocardial ischemia or previous silent infarction at the first stage (n = 439; 9.1%) were entered into the second stage, which included echocardiogram, thallium 201 scintigraphy in conjunction with exercise testing or dipyridamole test, exercise radionuclide ventriculography and ergonovine test. Three hundred eighty-seven men participated in the second stage; after the diagnostic procedures were performed, 104 men (2.1%) were still suspected of having type 1 silent myocardial ischemia or infarction on the basis of predefined criteria. Sixty-two men continued on into the third diagnostic workup including coronary angiography. The final diagnosis of type 1 silent myocardial ischemia or infarction was reached in 25 patients (prevalence 0.52%; adjusted estimate 0.89%). Of these 25, 19 had coronary atherosclerotic disease, 1 had Kawasaki disease, 1 had coronary anomaly, 1 had induced focal coronary spasm, and 2 had normal coronary arteriograms despite the presence of unquestionable old myocardial infarction. Altogether, 6 patients with silent myocardial infarction were identified.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND Several studies performed before the advent of thrombolysis have shown that the presence of ventricular arrhythmias is an independent risk factor for subsequent mortality in patients recovering from acute myocardial infarction. Since fibrinolysis affects the natural history of infarction and may alter the clinical relevance of different risk factors, the aim of the present study was to establish the prevalence and prognostic value of ventricular arrhythmias in post-myocardial infarction patients treated with fibrinolytic agents during the acute phase. METHODS AND RESULTS Twenty-four-hour Holter recordings obtained before discharge from the hospital in 8,676 post-myocardial infarction patients of the GISSI-2 study were analyzed for the presence of ventricular arrhythmias. Patients were followed for 6 months from the acute event; total and sudden cardiovascular mortality rates were computed, and relative risks in univariate and multivariate analyses were calculated. Ventricular arrhythmias were present in 64.1% of the patients, more than 10 premature ventricular beats per hour were recorded in 19.7% of the patients, and nonsustained ventricular tachycardia was present in 6.8% of the patients. Ventricular arrhythmias were more frequent when signs or symptoms of left ventricular damage were present. During follow-up, there was a total of 256 deaths 2.0% in patients without ventricular arrhythmias, 2.7% in patients with one to 10 premature ventricular beats per hour, 5.5% in those with more than 10 premature ventricular beats per hour, and 4.8% in those with complex premature ventricular beats. Even after adjusting for several risk factors, the presence of frequent (more than 10 premature ventricular beats per hour) ventricular arrhythmias remained a significant predictor of total (RRCox, 1.62; 95% confidence interval, 1.16-2.26) and sudden mortality (RRCox, 2.24; 95% confidence interval, 1.22-4.08). On the other hand, the presence of nonsustained ventricular tachycardia was not associated with a worsening of the prognosis in the adjusted analysis (RRCox, 1.20; 95% confidence interval, 0.80-1.79). CONCLUSIONS This study shows that approximately 36% of patients recovering from acute myocardial infarction presented with less than one premature ventricular beat per hour in Holter recordings obtained before discharge from the hospital, whereas almost 20% of patients showed frequent (more than 10 premature ventricular beats per hour) ventricular arrhythmias. Due to the large size of the population of this study, these figures may be used as a reliable estimate of the prevalence of arrhythmias in postinfarction patients treated with fibrinolytic agents during the acute phase. Frequent premature ventricular beats are confirmed as independent risk factors of total and sudden death in the first 6 months following the acute event; the significance of nonsustained ventricular tachycardia in this population appears more controversial.

The accuracy of sequential testing in the noninvasive diagnosis of coronary artery disease has been established in the symptomatic clinical populations, while little is known about its value when applied to low prevalence groups, such as totally asymptomatic men. To evaluate the accuracy of noninvasive sequential testing in the diagnosis of silent myocardial ischemia, data were collected from exercise electrocardiogram, 201Tl perfusion scintigraphy and radionuclide angiography for 62 totally asymptomatic middle-aged men who underwent coronary arteriography because they were positive for two or more markers of myocardial ischemia as determined by a diagnostic screening of a nonbiased population consisting of 4,842 presumably healthy men aged 40-59 years (the ECCIS Project). The predictive value of serial testing procedures for significant coronary artery obstruction was 35%. Predictive values of an abnormal electrocardiogram associated with either an abnormal 201Tl scintigram, an abnormal isotopic ventriculography, or both were 33, 38 and 31%, respectively. In asymptomatic middle-aged men, there is at least a 50% likelihood that an abnormal radionuclide test is a false-positive result, and the positive predictive value is not enhanced by the concordance of an abnormal 201Tl scintigraphy with an abnormal isotopic ventriculography. Thus, the application of noninvasive sequential testing in screening for asymptomatic coronary artery disease is limited by its low predictive value in accordance with the Bayesian probability theory.

An epidemiological study was conducted on 5163 men aged 40–59 years, made by occupational samples, from Florence and Rome to identify, by a three-stage procedure, subjects with asymptomatic silent ischemic heart disease (SIHD). This report describes some coronary risk factors. Men who are free from heart disease were compared with: (1) those having a low probability of SIHD (ECG signs only; n = 439); (2) those having a high probability of SIHD (ECG signs plus echographic signs, or positive markers of deficient perfusion, or altered radionuclide ventriculography; n = 104); (3) those having a definite SIHD (signs of the first two groups plus evidence from coronary angiography; n = 25). A clearcut increasing trend in the levels of major coronary risk factors, and in the multivariate estimated coronary risk for major events was found. The difference was not significant between highly probabile and definite cases of SIHD, due to the small numbers involved. Three multiple logistic models, with the three probability levels of silent ischemia as end-points, showed that four of 10 tested factors were associated with the presence of SIHD: age, systolic blood pressure, cigarette smoking and non-HDL serum cholesterol.

A multicentre, randomised, open trial with a 2 x 2 factorial design was conducted to compare the benefits and risks of two thrombolytic agents, streptokinase (SK, 1·5 MU infused intravenously over 30-60 min) and alteplase (tPA, 100 mg infused intravenously over 3 h) in patients with acute myocardial infarction admitted to coronary care units within 6 h from onset of symptoms. The patients were also randomised to receive heparin (12 500 U subcutaneously twice daily until discharge from hospital, starting 12 h after beginning the tPA or SK infusion) or usual therapy. All patients without specific contraindications were given atenolol (5-10 mg iv) and aspirin (300-325 mg a day). The end-point of the study was the combined estimate of death plus severe left ventricular damage. 12 490 patients were randomised to four treatment groups (SK alone, SK plus heparin, tPA alone, tPA plus heparin). No specific differences between the two thrombolytic agents were detected as regards the combined end-point (tPA 23·1%; SK 22·5%; relative risk 1·04, 95% Cl 0·95-1·13), nor after the addition of heparin to the aspirin treatment (hep 22·7%, no hep 22·9%; RR 0·99, 95% Cl 0·91-1·08). The outcome of patients allocated to the four treatment groups was similar with respect to baseline risk factors such as age, Killip class, hours from onset of symptoms, and site and type of infarct. The rates of major in-hospital cardiac complications (reinfarction, post-infarction angina) were also similar. The incidence of major bleeds was significantly higher in SK and heparin treated patients (respectively, tPA 0·5%, SK 1·0%, RR 0·57, 95% Cl 0·38-0·85; hep 1·0%, no hep 0·6%, RR 1·64, 95% Cl 1·09-2·45), whereas the overall incidence of stroke was similar in all groups. SK and tPA appear equally effective and safe for use in routine conditions of care, in all infarct patients who have no contraindications, with or without post-thrombolytic heparin treatment. The 8·8% hospital mortality of the study population (compared with approximately 13% in the control cohort of the GISSI-1 trial) indicates the beneficial impact of the proven acute treatments for AMI.

In the GISSI trial, 11,712 patients with acute myocardial infarction were randomized to receive either standard care or standard care with 1.5 million units streptokinase intravenously. A highly significant reduction in mortality during hospitalization in streptokinase-treated patients was observed. The mortality at 1 year was determined in 98.3% of the patients who had been originally randomized; the 1 year mortality of patients discharged alive was similar in those patients treated with streptokinase and those who were not; that is, the beneficial effects of streptokinase treatment on survival that were observed in the hospital phase of the study persisted unchanged and with comparable statistical significance for 1 year. However, a higher incidence of reinfarction occurred in the treated versus the control groups both during the hospital phase and at the 6 month follow-up. Streptokinase treatment had no detectable effect in patients with a history of previous infarction.

In order to evaluate whether or not criteria for surgical revascularization in patients with early post-infarction angina (EPIA) should be different from those commonly used for patients with angina, the incidence and prognostic implications of EPIA were analysed in 188 AMI patients in Killip's class I or II on admission. Sixty-two patients (33%) complained of EPIA (Group I) and 126 patients were symptom-free (Group II). There were no differences between the two groups in in-hospital and late mortality and reinfarction. On the contrary, severity of angina was significantly associated with the occurrence of in-hospital and late cardiac death, reinfarction and revascularization procedures. EPIA patients underwent revascularization procedures significantly more frequently than group II patients, both during hospitalization (29% versus 1%; P less than 0.001) and follow up (10% versus 1%; P less than 0.01). Coronary artery involvement was significantly more severe in group I than in group II and in the operated patients compared with the non-operated ones. Our data suggest that the severity of angina should be the leading criterion for surgery, as it is able to identify most of the patients with severe coronary artery disease and poor prognosis.

To evaluate the different contributions of infarct site and infarct extent in determining the in-hospital outcome and efficacy of thrombolytic therapy, 8,731 patients with a first Q-wave acute myocardial infarction (AMI) enrolled in the GISSI trial were studied. On the basis of the standard 12-lead electrocardiogram, the sample was classified in 2 ways: classic electrocardiographic site pattern (anterior, inferior, lateral and multiple location), and number of standard electrocardiographic leads with ischemic ST elevation (small, modest, large and extensive infarct in 2 to 9 leads). In-hospital mortality was evaluated according to infarct site, infarct extent and fibrinolytic treatment. The mortality rate was differently distributed in the various infarct sites. Streptokinase significantly reduced mortality only in anterior (13.8 vs 18.7%) and multiple site infarcts (8.1 vs 12.5%). According to the infarct extent observed, there is a progressive increase in the mortality rate—from 6.5% in small infarcts to 9.6% in modest, 14.3% in large and 21.7% in extensive. No significant benefit was obtained by streptokinase in small infarcts; in contrast, a significant decrease in mortality was achieved in modest (7.7 vs 11.4%), large (12.8 vs 16.6%) and extensive infarcts (19.5 vs 23.9%). Thus, the extent of myocardial injury seems to be more relevant than the site in determining in-hospital mortality and efficacy of thrombolytic therapy.

Background: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). Methods: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. Results: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. Conclusions: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

It has been demonstrated that antitumor immune response is an IL-2-dependent phenomenon. Moreover, experimental results suggest the existence of interactions between IL-2 and the pineal gland, which also plays a role in the control of immunity and cancer growth. Alterations of both IL-2 and melatonin secretion have been reported in cancer patients. To further investigate pineal/IL-2 relationships in humans with cancer, we evaluated the melatonin rhythm in seven advanced small cell lung cancer patients, before and at weekly intervals during immunotherapy with IL-2, given subcutaneously at a daily dose of 3 × 106 IU/m2 twice daily for 5 days/week for 4 weeks. Before IL-2, no patient showed a light/dark rhythm of melatonin. IL-2 administration induced a normalization of the melatonin circadian rhythm, with the appearance of a night time peak in 4/7 patients. This effect, however, disappeared with IL-2 interruption in 3/4 patients. This preliminary study, by showing that IL-2 may restore a normal melatonin rhythm, suggests that the anomalous pineal function in cancer may depend at least in part on the altered endogenous IL-2 production.

The recent advances in the knowledge of the psychoneuroimmunological pathogenesis of human neoplasms have demonstrated the existence of feed-back mechanisms operating between interleukins and endocrine secretions, which play an important role in the regulation of the immune responses, including the anticancer immunity. In contrast, few studies only have been performed to investigate the possible relation between endocrine activities and hematopoietic growth factors. The present study was performed to analyze the acute endocrine effects of erythropoietin-alpha (EPO) on the main endocrine secretions. The study was carried out in 10 advanced solid tumor patients. EPO was injected subcutaneously at a dose of 10,000 U, and venous blood samples were collected before and 2, 4 and 6 h after EPO administration. No significant changes in mean serum levels of FSH, LH and TSH were seen in response to EPO. Cortisol and DHEAS concentrations increased after EPO injection, whereas those of PRL decreased, but none of these differences was statistically significant. Finally, mean serum levels of both growth hormone (GH) and somatomedin-C (IGF-1) significantly decreased after EPO administration. This preliminary study shows that EPO may inhibit GH secretion from the pituitary gland and IGF-1 production. Since GH would stimulate EPO release, the results of this study may suggest the existence of feedback mechanism operating between GH secretion and EPO production, with inhibitory effect of EPO on GH secretion, and stimulatory action of GH on EPO production. Therefore, this study would describe the first example of hemato-endocrine feedback mechanisms. Moreover, this study, by showing an inhibitory effect of EPO on IGF-1 secretion, would suggest a possible use of EPO in the medical oncology not only for the treatment of cancer related anemia, but also to counteract tumor growth by blocking IGF-1 production, which has been proven to be a growth factor for several tumor histotypes. Obviously, IGF-1 is not the only tumor growth factor, but it could play a fundamental role in the regulation of production and activity of several other tumor growth factors. In any case, this study describes the only acute endocrine effects of EPO. Therefore, further studies, by evaluating the endocrine effects of a chronic treatment with EPO, will be required to establish which may be its effect on IGF-1 endogenous production, and its consequence on survival time.

The advanced tumours of the digestive tract are generally less responsive to conventional chemotherapies. Moreover, preliminary results with IL-2 immunotherapy also seem to show a low efficacy. On the basis of our previous studies suggesting s synergistic action between IL-2 and some neurohormones, such as the pineal indole MLT, a clinical trial was performed to investigate the clinical efficacy and tolerability of an immunotherapy with IL-2 plus MLT in patients with advanced neoplasms of the digestive tract. The study included 35 patients (colorectal cancer: 14; gastric cancer: 8; hepatocarcinoma: 6; pancreas adenocarcinoma: 7). Distant organ metastases were present in 31/35 patients. MLT was given orally at a daily dose of 50 mg at 8.00 p.m., starting 7 days before IL-2, which was given subcutaneously at a dose of 3 million IU/day at 8.00 p.m. for 6 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In nonprogressed patients, a second cycle was given after a 21-day rest period. A complete response was achieved in two patients (gastric cancer: 1; hepatocarcinoma: 1). Six other patients obtained a partial response: (gastric cancer: 2; hepatocarcinoma: 2; colon cancer: 1; pancreas cancer: 1). Therefore, the overall response rate was 8/35 (23%). Stable disease was obtained in 11/35 (31%) patients, whereas the remaining 16 patients (46%) progressed. The response rate was significantly higher in untreated patients than in those previously treated with chemotherapy. Toxicity was low in all patients, who received the treatment as a home therapy. This study shows that the immunotherapy with low-dose IL-2 plus the pineal hormone MLT is a new well tolerated and effective therapy of advanced tumours of the digestive tract, mainly in gastric cancer and hepatocarcinoma.

Interleukin-2 has been shown to stimulate Cortisol secretion in man. Owing to its Immunosuppressive properties, an increase in Cortisol levels during interleukin-2 cancer immunotherapy could potentially counteract induced activation of the antitumor immune response. Few data are available about Cortisol secretion secondary to prolonged interleukin-2 administration. To Investigate the problem, we evaluated Cortisol circadian rhythms in 7 consecutive metastatic small cell lung cancer patients who received interleukin-2 subcutaneously for 4 weeks (daily dose: 6 × 106 × IU/m2). Venous blood samples were drawn at 8.00 a.m., 4.00 p.m. and 12.00 p.m., before Interleukin-2, and after each week until the end of the cycle. Beta-endorphin levels were also measured on the same samples. Four patients were evaluated during a second interleukin-2 cycle. Mean Cortisol levels increased during Interleukin-2 therapy, but were significantly higher than those seen in basal conditions after the first week of treatment. Moreover, Cortisol peaks observed during the second cycle of therapy were not significantly different from those seen during the first cycle. Mean beta-endorphin levels increased in response to interleukin-2 administration, but the increase did not reach statistical significance. The early Cortisol rise progressively decreased as treatment continued. This suggests that the interleukin-2-induced Cortisol rise has no relevant clinical importance in antagonizing the activation of an effective antitumor immune response during cancer immunotherapy with interleukin-2.