Evaluation of methodologies to determine the effect of specific active immunotherapy on VEGF levels in phase I clinical trial patients with advanced solid tumors.

Two phase I clinical trials were conducted to evaluate, among other parameters, the humoral response elicited by a vascular endothelial growth factor (VEGF)-based therapeutic vaccine in cancer patients with advanced solid tumors. VEGF reduction was studied using an indirect methodology named as "Platelet VEGF". This methodology is based on the estimation of VEGF within platelets by subtracting the plasma VEGF level from the serum level and dividing this by the platelet count, and then this latter expression is additionally corrected by the hematocrit. However, there is broad debate, whether serum or plasma VEGF or platelet-derived VEGF measurements is the most appropriate strategy to study the changes that occur on ligand bioavailability when patients are submitted to a VEGF-based immunotherapy. The current research is a retrospective study evaluating the changes on VEGF levels in serum and plasma as well as platelet-derived measurements. Changes in VEGF levels were related with the humoral response seen in cancer patients after an active immunotherapy with a VEGF-based vaccine. The present study indicates that "Platelet VEGF" is the most reliable methodology to investigate the effect of VEGF-based immunotherapies on ligand bioavailability. "Platelet VEGF" was associated with those groups of individuals that exhibited the best specific humoral response and the variation of "Platelet VEGF" showed the strongest negative correlation with VEGF-specific IgG antibody levels. This methodology will be very useful for the investigation of this VEGF-based vaccine in phase II clinical trials and could be applied to immunotherapies directed to other growth factors that are actively sequestered by platelets.

Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants.

BACKGROUND: CIGB-247, a VSSP-adjuvanted VEGF-based vaccine, was evaluated in a phase I clinical trial in patients with advanced solid tumors (CENTAURO). Vaccination with the maximum dose of antigen showed an excellent safety profile, exhibited the highest immunogenicity and was the only one showing a reduction on platelet VEGF bioavailability. However, this antigen dose level did not achieve a complete seroconversion rate in vaccinated patients. These clinical results led us to the question whether a "reserve" of untapped immune response potential against VEGF could exist in cancer patients. To address this matter, CENTAURO-2 clinical trial was conducted where antigen and VSSP dose scale up were studied, and also incorporated the exploration of aluminum phosphate as adjuvant. These changes were made with the aim to increase immune response against VEGF. RESULTS: The present study reports the characterization of the humoral response elicited by CIGB-247 from the combining of different antigen doses and adjuvants. Cancer patients were immunologically monitored for approximately 1 year. Vaccination with different CIGB-247 formulations exhibited a very positive safety profile. Cancer patients developed IgM, IgG or IgA antibodies specific to VEGF. Elicited polyclonal antibodies had the ability to block the interaction between VEGF and its receptors, VEGFR1 and VEGFR2. The highest humoral response was detected in patients immunized with 800 µg of antigen + 200 µg of VSSP. Off-protocol long-term vaccination did not produce negative changes in humoral response. CONCLUSIONS: Vaccination with a human VEGF variant molecule as antigen in combination with VSSP or aluminum phosphate is immunogenic. The results of this study could contribute to the investigation of this vaccine therapy in an adequately powered efficacy trial. TRIAL REGISTRATION: Trial registration number: RPCEC00000155. Cuban Public Clinical Trial Registry. Date of registration: June 06, 2013. Available from: http://registroclinico.sld.cu/ .

Recombinant streptokinase vs hydrocortisone suppositories in acute hemorrhoids: A randomized controlled trial.

AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) vs hydrocortisone acetate-based suppositories in acute hemorrhoidal disease. METHODS: A multicenter (11 sites), randomized (1:1:1), open, controlled trial with parallel groups was performed. All participating patients gave their written, informed consent. After inclusion, patients with acute symptoms of hemorrhoids were centrally randomized to receive, as outpatients, by the rectal route, suppositories of rSK 200000 IU of one unit every 8 h (first 3 units) and afterwards every 12 h until 8 administrations were completed (schedule A), one unit every 8 h until 6 units were completed (schedule B), or 25 mg hydrocortisone acetate once every 8 h up to a maximum of 24 administrations. Evaluations were performed at 3, 5, and 10 d post-inclusion. The main end-point was the 5(th)-day response (disappearance of pain and bleeding, and ≥ 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were also evaluated. RESULTS: Groups were homogeneous with regards to demographic and baseline characteristics. Fifth day complete response rates were 156/170 (91.8%; 95%CI: 87.3-96.2), 155/170 (91.2%; 95%CI: 86.6%-95.7%), and 46/170 (27.1%; 95%CI: 20.1%-34.0%) with rSK (schedule A and B) and hydrocortisone acetate suppositories, respectively. These 64.6% and 63.9% differences (95%CI: 56.7%-72.2% and 55.7%-72.0%) were highly significant (P < 0.001). This advantage was detected since the early 3(rd) day evaluation (68.8% and 64.1% vs 7.1% for the rSK and active control groups, respectively; P < 0.001) and was maintained even at the late 10(th) day assessment (97.1% and 93.5% vs 67.1% for rSK and hydrocortisone acetate, respectively; P < 0.001). Time to response was 3 d (95%CI: 2.9-3.1) for both rSK groups and 10 d (95%CI: 9.3-10.7) in the hydrocortisone acetate group. This difference was highly significant (P < 0.001). All subgroup stratified analyses (with or without thrombosis and hemorrhoid classification) showed a statistically significant advantage for the rSK groups. Thrombectomy was necessary in 4/251 and 14/133 patients with baseline thrombosis in the rSK and hydrocortisone acetate groups, respectively (P < 0.001). There were no adverse events attributable to the experimental treatment. CONCLUSION: rSK suppositories showed a significant advantage over a widely-used over-the-counter hydrocortisone acetate preparation for the treatment of acute hemorrhoidal illness, as well as having an adequate safety profile.

Caracterización epidemiológica de la enfermedad hemorroidal aguda en hospitales seleccionados en Cuba (noviembre de 2011 a enero 2012) / Epidemiological characterization of acute hemorrhoidal disease in selected hospitals in Cuba (November 2011 to January 2012)

Introducción: la enfermedad hemorroidal constituye un problema de salud mundial y Cuba; sin embargo, la literatura no recoge información epidemiológica sobre la población cubana. Por lo que este trabajo caracteriza la enfermedad hemorroidal aguda en hospitales cubanos seleccionados, con particular énfasis en los factores de riesgo que favorecen su aparición. Objetivos: identificar los principales factores de riesgo, sus características demográficas y de base; hábitos tóxicos y alimenticios, así como modos y estilos de vida, que favorecen la aparición de una enfermedad hemorroidal aguda. Métodos: se realizó un estudio observacional descriptivo en 11 servicios cubanos de Coloproctología. Se incluyeron 510 pacientes con diagnóstico de enfermedad hemorroidal aguda, con edades comprendidas entre 18 y 75 años, que dieron su consentimiento de participación en el estudio. A todos los pacientes se les aplicó una encuesta epidemiológica que indagaba acerca de los hábitos tóxicos y alimenticios, así como modos y estilos de vida, los cuales son reconocidos como factores de riesgo para la aparición de la enfermedad. Resultados: casi el 75 por ciento de los pacientes comenzó con la enfermedad. Predominaron las hemorroides externas y los signos y síntomas más frecuentes fueron el dolor anal, la sensación de masa, el edema y el sangramiento rectal. La mitad de los pacientes ingiere bebidas alcohólicas y la mayoría consume café, alimentos condimentados y requiere una posición erecta o permanecer sentado durante largos períodos de tiempo, para sus actividades cotidianas. Pocos pacientes consumen altos contenidos de fibras en la dieta, así como abundante agua. Conclusiones: se corrobora la presencia de factores de riesgo e inadecuados modos y estilos de vida en la población cubana que facilitan o propician la aparición de un episodio agudo hemorroidal(AU)

Introduction: hemorrhoidal disease is a global health problem. In Cuba, however, epidemiological data about the population is not available in the literature on the subject. That is the reason why the present paper is aimed at characterizing acute hemorrhoidal disease in selected Cuban hospitals, with particular emphasis on the risk factors leading to its appearance. Objectives: identify the main risk factors, demographic and base features, toxic and eating habits, and life styles and modes, leading to the appearance of acute hemorrhoidal disease. Methods: an observational descriptive study was conducted in 11 Cuban coloproctology services. The sample consisted of 510 patients aged 18-75 diagnosed with acute hemorrhoidal disease, who gave their consent to participate in the study. All patients were given an epidemiological survey about toxic and eating habits, and life styles and modes perceived as risk factors for the disease. Results: almost 75 percent of the patients developed the disease. There was a predominance of external hemorrhoids, and the most common signs and symptoms were anal pain, mass sensation, edema and rectal bleeding. Half the patients consume alcohol and most drink coffee, eat spicy foods and must remain in a standing or sitting position for long periods during their daily activities. Few patients consume a fiber-rich diet and abundant water. Conclusions: corroboration was made of the presence of risk factors and inadequate life styles and modes among the Cuban population which lead to the occurrence of acute hemorrhoidal episodes(AU)

Caracterización epidemiológica de la enfermedad hemorroidal aguda en hospitales seleccionados en Cuba (noviembre de 2011 a enero 2012) / Epidemiological characterization of acute hemorrhoidal disease in selected hospitals in Cuba (November 2011 to January 2012)

Introducción: la enfermedad hemorroidal constituye un problema de salud mundial y Cuba; sin embargo, la literatura no recoge información epidemiológica sobre la población cubana. Por lo que este trabajo caracteriza la enfermedad hemorroidal aguda en hospitales cubanos seleccionados, con particular énfasis en los factores de riesgo que favorecen su aparición. Objetivos: identificar los principales factores de riesgo, sus características demográficas y de base; hábitos tóxicos y alimenticios, así como modos y estilos de vida, que favorecen la aparición de una enfermedad hemorroidal aguda. Métodos: se realizó un estudio observacional descriptivo en 11 servicios cubanos de Coloproctología. Se incluyeron 510 pacientes con diagnóstico de enfermedad hemorroidal aguda, con edades comprendidas entre 18 y 75 años, que dieron su consentimiento de participación en el estudio. A todos los pacientes se les aplicó una encuesta epidemiológica que indagaba acerca de los hábitos tóxicos y alimenticios, así como modos y estilos de vida, los cuales son reconocidos como factores de riesgo para la aparición de la enfermedad. Resultados: casi el 75 por ciento de los pacientes comenzó con la enfermedad. Predominaron las hemorroides externas y los signos y síntomas más frecuentes fueron el dolor anal, la sensación de masa, el edema y el sangramiento rectal. La mitad de los pacientes ingiere bebidas alcohólicas y la mayoría consume café, alimentos condimentados y requiere una posición erecta o permanecer sentado durante largos períodos de tiempo, para sus actividades cotidianas. Pocos pacientes consumen altos contenidos de fibras en la dieta, así como abundante agua. Conclusiones: se corrobora la presencia de factores de riesgo e inadecuados modos y estilos de vida en la población cubana que facilitan o propician la aparición de un episodio agudo hemorroidal(AU)

Introduction: hemorrhoidal disease is a global health problem. In Cuba, however, epidemiological data about the population is not available in the literature on the subject. That is the reason why the present paper is aimed at characterizing acute hemorrhoidal disease in selected Cuban hospitals, with particular emphasis on the risk factors leading to its appearance. Objectives: identify the main risk factors, demographic and base features, toxic and eating habits, and life styles and modes, leading to the appearance of acute hemorrhoidal disease. Methods: an observational descriptive study was conducted in 11 Cuban coloproctology services. The sample consisted of 510 patients aged 18-75 diagnosed with acute hemorrhoidal disease, who gave their consent to participate in the study. All patients were given an epidemiological survey about toxic and eating habits, and life styles and modes perceived as risk factors for the disease. Results: almost 75 percent of the patients developed the disease. There was a predominance of external hemorrhoids, and the most common signs and symptoms were anal pain, mass sensation, edema and rectal bleeding. Half the patients consume alcohol and most drink coffee, eat spicy foods and must remain in a standing or sitting position for long periods during their daily activities. Few patients consume a fiber-rich diet and abundant water. Conclusions: corroboration was made of the presence of risk factors and inadequate life styles and modes among the Cuban population which lead to the occurrence of acute hemorrhoidal episodes(AU)

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study.

BACKGROUND: Interferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers. METHODS: A randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria. RESULTS: The pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h(-1); mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild. CONCLUSIONS: Both formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.