Specific active immunotherapy with a VEGF vaccine in patients with advanced solid tumors. results of the CENTAURO antigen dose escalation phase I clinical trial.

CIGB-247 is a novel cancer therapeutic vaccine that uses a human VEGF variant molecule as antigen, in combination with a bacterial adjuvant. In mice, CIGB-247 has anti-tumor and anti-metastatic effects. The vaccine induces anti-VEGF blocking antibodies and a cellular response targeting tumor cells producing VEGF, and has proven to be safe in mice, rats, rabbits and non-human primates. Herein we report the results of a Phase I clinical trial (code name CENTAURO) where safety, tolerance, and immunogenicity of CIGB-247 were studied in 30 patients with advanced solid tumors, at three antigen dose levels. Individuals were subcutaneously immunized for 8 consecutive weeks with 50, 100 or 400 µg of antigen, and re-immunized on week twelve. On week sixteen, evaluations of safety, tolerance, clinical status, and immunogenicity (seroconversion for anti-VEGF IgG, serum VEGF/KDR-Fc blocking ability, and gamma-IFN ELISPOT with blood cells stimulated in vitro with mutated VEGF) were done. Surviving patients were eligible for off-trial additional 4-week re-immunizations with 400 µg of antigen. Immunogenicity and clinical status were again studied on weeks 25 and 49. Vaccination was shown to be safe at the three dose levels, with only grade 1-2 adverse events. CIGB-247 was immunogenic and higher numbers of individuals positive to the three immune response tests were seen with increasing antigen dose. Off-protocol long-term vaccination produced no additional adverse events or negative changes in immunogenicity. Eleven patients are still alive, with overall survivals ranging from 20 to 24 months. Twelve of the thirty patients exhibited objective clinical benefits, and two individuals have complete responses. Most patients with higher survivals are positive in the three immune response tests. In summary, this is the first clinical testing report of a cancer therapeutic vaccine based on a human VEGF related molecule as antigen. The CIGB-247 vaccine is safe, immunogenic, and merits further clinical development. REGISTRATION NUMBER AND NAME OF TRIAL REGISTRY: RPCEC00000102. Cuban Public Clinical Trial Registry (WHO accepted Primary Registry). Available from: http://registroclinico.sld.cu/.

Recombinant streptokinase suppositories in the treatment of acute haemorrhoidal disease. Multicentre randomized double-blind placebo-controlled trial (THERESA-2).

AIM: A four-arm multicentre randomized double-blind placebo-controlled trial was undertaken to assess the effect and safety of suppositories containing recombinant streptokinase (rSK) at two dose levels (100,000 IU and 200,000 IU) with sodium salicylate (SS) compared with placebo and SS for the treatment of acute haemorrhoidal disease. METHOD: Patients with acute symptoms of haemorrhoids were randomized to four treatment groups: (I) placebo, (II) SS, (III) SS + rSK 100,000 IU and (IV) SS + rSK 200,000 IU per suppository. Inpatient treatment was by four suppositories given every 6 h to discharge at 24 h. Evaluations were made at the time of discharge (24 h) and at 3, 5 and 20 days later. The main end-point was the degree of relief of pain, oedema and reduction in the size of the lesion by 90% on day 5. Adverse events and the occurrence of anti-SK antibodies were also determined. RESULTS: Eighty patients were included. Respective response rates in the four groups were 16%, 30%, 25% and 52%. In the last group there was a significant difference (36.8%) compared with control (95% CI 7.0-58.4%). The time to response was significantly shorter (median 5 days) in the 200,000 IU rSK group with respect to the others. There were no adverse events attributable to the treatment. No increase in anti-SK antibodies was detected 20 days after treatment. CONCLUSION: Suppositories with 200,000 IU rSK showed a significant improvement in symptoms of acute haemorrhoids, with an adequate safety profile.

A multicenter, randomized, double-blind clinical trial examining the effect of oral human recombinant epidermal growth factor on the healing of duodenal ulcers.

BACKGROUND: Our aim was to study the efficacy of oral human recombinant epidermal growth factor (EGF) in the treatment of duodenal ulcers, on the basis of its repairing actions in the gastrointestinal tract. METHODS: A placebo-controlled, multicenter, randomized, and double-blind study was conducted. Treatment groups were A) placebo solution, B) 10 microg/ml of human recombinant (hr)-EGF, and C) 50 microg/ml of hr-EGF, three times daily during 6 weeks. Patients, 15-65 years old, with a duodenal ulcer >4 mm, who gave their written informed consent to participate were eligible. Exclusion criteria were gastric ulcer and more than one duodenal ulcer, ulcer-related complications, and previous treatment with oral EGF or other specific anti-ulcer drugs in the previous 2 weeks. The main outcome variable was ulcer healing, evaluated by endoscopy after the 2nd, 4th, and 6th week. RESULTS: One hundred and three patients were included. The groups were comparable with regard to age, sex, toxic habits, antecedents of ulcerous disease, initial size and depth or the ulcer, initial symptoms, and positivity for Helicobacter pylori. The ulcers were healed in a larger proportion of patients treated with hr-EGF at the highest dose (70.6% in group C versus 40.0% and 35.3% in placebo and low-dose groups, respectively (P = 0.007)). The difference was significant from week 4 on. Groups A and B did not differ. Eighty-eight percent of group C patients were cured or improved versus 57% and 56% in groups A and B, respectively. No adverse reactions were reported. CONCLUSIONS: Oral hr-EGF was effective in the treatment of duodenal ulcer at a 50-microg/ml dose every 8 h but not at 10 microg/ml.

Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study.

AIMS: It is as yet undefined whether simple indexes of autonomic balance such as heart rate (HR) may play a role in risk stratification in patients with acute myocardial infarction (MI). The aim of this study was to quantify the prognostic significance of HR from the surface ECG obtained both at entry and at discharge, in a large population of patients all treated with fibrinolysis during the acute phase and having confirmed acute MI. METHODS AND RESULTS: Surface ECGs obtained at entry and at discharge in patients with confirmed MI enrolled in the GISSI-2 study, a large multicentre trial of different thrombolytic agents, were retrieved. Heart rhythm was evaluated and HR was measured; these data were then added to the main database of GISSI-2 allowing a complete evaluation of the prognostic significance of HR. Patients not in sinus rhythm or with grade 2-3 atrioventricular block were excluded. The prognostic significance of HR (cut-offs predefined at 60, 80, 100 beats.min-1) at entry for in-hospital mortality and at discharge for 6-month mortality was evaluated in the general population and in predefined subgroups. Multivariate analyses were used to assess the independent prognostic value of HR. A total of 8915 patients (more than 70% of the original population) were suitable for the analysis. There was a progressive increase in mortality with increasing HR in the general population (from 7.1% for HR < 60 beats.min-1) to 23.4% for HR > 100 beats.min-1) and in the predefined subgroups. Multivariate analysis showed that HR exerted an independent prognostic significance. Data for analysis of HR at discharge were available for 7831 patients. Consistent with the data observed at entry, a progressive increase of 6-month mortality with increasing HR was present in the general population (from 0.8% for HR < 60 beats.min-1) to 14.3% for HR > 100 beats.min-1) and for the different predefined subgroups. Multivariate analysis confirmed the independent prognostic significance of HR. There was no relation between HR and the incidence of fatal and non-fatal reinfarction. CONCLUSION: The present study indicates that HR values from a standard 12-lead ECG independently predict mortality in patients with acute MI during the in-hospital phase and after discharge. This simple index appears very useful for risk stratification in clinical practice.