A phase II dose-escalation trial of perioperative desmopressin (1-desamino-8-d-arginine vasopressin) in breast cancer patients

Desmopressin (dDAVP) is a well-known peptide analog of the antidiuretic hormone vasopressin, used to prevent excessive bleeding during surgical procedures. dDAVP increases hemostatic mediators, such as the von Willebrand factor (vWF), recently considered a key element in resistance to metastasis. Studies in mouse models and veterinary trials in dogs with locally-advanced mammary tumors demonstrated that high doses of perioperative dDAVP inhibited lymph node and early blood-borne metastasis and significantly prolonged survival. We conducted a phase II dose-escalation trial in patients with breast cancer, administering a lyophilized formulation of dDAVP by intravenous infusion in saline, 30–60 min before and 24 h after surgical resection. Primary endpoints were safety and tolerability, as well as selection of the best dose for cancer surgery. Secondary endpoints included surgical bleeding, plasma levels of vWF, and circulating tumor cells (CTCs) as measured by quantitative PCR of cytokeratin-19 transcripts. Only 2 of a total of 20 patients experienced reversible adverse events, including hyponatremia (grade 4) and hypersensitivity reaction (grade 2). Reactions were adequately managed by slowing the infusion rate. A reduced intraoperative bleeding was noted with increasing doses of dDAVP. Treatment was associated with higher vWF plasma levels and a postoperative drop in CTC counts. At the highest dose level evaluated (2 μg/kg) dDAVP appeared safe when administered in two slow infusions of 1 μg/kg, before and after surgery. Clinical trials to establish the effectiveness of adjunctive perioperative dDAVP therapy are warranted. This trial is registered on www.clinicaltrials.gov (NCT01606072).Fil: Weinberg, Ruth S.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Grecco, Marcelo O.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Ferro, Gimena S.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Seigelshifer, Debora Judith. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Perroni, Nancy V.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Terrier, Francisco J.. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Maronna, Esteban. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Sánchez Marull, Ricardo. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Frahm, Isabel. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Guthmann, Marcelo D.. Laboratorio Elea; ArgentinaFil: Di Leo, Daniela. Laboratorio Elea; ArgentinaFil: Spitzer, Eduardo. Laboratorio Elea; ArgentinaFil: Ciccia, Graciela Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Pifano, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Torbidoni, Ana Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Ripoll, Giselle Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Roberto E.. Laboratorio Elea; ArgentinaFil: Demarco, Ignacio A.. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentin

Cellular and humoral immune response to N-glycolyl-GM3 elicited by prolonged immunotherapy with an anti-idiotypic vaccine in high-risk and metastatic breast cancer patients

In this study, the immunogenicity and toxicity profile of 1E10, an anti-idiotypic vaccine mimicking the N-glycolyl-GM3 ganglioside, was investigated with an extended vaccination protocol. The year-long vaccination scheme consisted of 6 biweekly intradermal injections (induction phase), followed by 10 monthly boosters (maintenance). Nineteen patients with high-risk (stage III) or metastatic breast cancer were vaccinated with different dose levels of 1E10 (0.5, 1, and 2 mg). The humoral and cellular responses to 1E10 and the targeted ganglioside were assessed at baseline and throughout the treatment. Local skin reactions represented the most common adverse event (National Cancer Institute Toxicity Criteria (NCIC) grades I and II), followed by mild flu-like symptoms lasting for 1 to 2 days. Two patients were removed from the study because of vaccine-related hypersensitivity reactions. A third patient was removed from the study after a transient loss of consciousness with uncertain relation to the vaccine. All patients showed a strong antibody response to the targeted ganglioside. In addition, ganglioside-specific T-cell responses were recorded in 5 of 13 evaluable patients. Vaccination with 1E10 was immunogenic and relatively well tolerated. Because similar results were observed with the 3 tested dose levels, the 0.5-mg dose level was selected for future trials.Fil: Guthmann, Marcelo D.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Castro, Mónica A.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cinat, Gabriela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Venier, Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Koliren, Leonardo. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Bitton, Roberto J.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Vázquez, Ana María. Center Of Molecular Immunology; CubaFil: Fainboim, Leonardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentin

Usefulness of Different Mortality Risk Scores in Patients with Heart Failure. A Retrospective and Observational Study

Background: The Cardiac and Comorbid Conditions - Heart Failure (3C-HF) and the Meta-Analysis Global Group in ChronicHeart Failure (MAGGIC) are two score models developed to predict mortality in patients with heart failure (HF). The performanceof these scores has been little studied in our setting.Objective: The aim of this study was to assess the performance of the 3C-HF and the MAGGIC scores to predict one-yearmortality in a population of patients with HF.Methods: Ambulatory HF patients discharged after hospitalization due to acute HF in two centers were included in the study.The 3C-HF and MAGGIC scores were calculated and one-year mortality was the study endpoint. The discrimination abilityof the scores was analyzed from the calculated area under the ROC curve and their calibration quality was assessed applyingthe Hosmer-Lemeshow test. Both areas under the ROC curve were compared using the Hanley-Mc Neil test.Results: A total of 704 patients with mean age of 73±11 years and 39.6% women were included in the study. One-year mortalitywas 12.4% (n=87). Both scores were independent predictors of mortality, with HR of 1.03 (95% CI 1.008-1.06; p=0.02)and 1.08 (95% CI 1.02-1.13; p=0.004) for the 3C-HF and MAGGIC scores, respectively. The area under the ROC curve for the3C-HF score was 0.70 (95% CI 0.64-0.75) and for the MAGGIC score 0.67 (95% CI 0.61-0.73), without significant differencesbetween them (p=0.41). Both scores presented adequate calibration (p=0.06 and p=0.32, respectively).Conclusion: The 3C-HF and MAGGIC scores were predictors of one-year mortality, with a moderate ability to discriminateevents and adequate calibration. The discrimination ability between both scores was not significant.Introducción: El Cardiac and Comorbid Conditions - Heart Failure (3C-HF) y el Meta-Analysis Global Group in Chronic HeartFailure (MAGGIC) son dos sistemas de puntaje desarrollados para predecir la mortalidad en pacientes con insuficiencia cardíaca(IC). El desempeño de estos puntajes ha sido poco estudiado en nuestro medio.Objetivo: Evaluar el desempeño del 3C-HF y del MAGGIC para predecir la mortalidad al año en una población de pacientescon IC.Material y métodos: Se incluyeron pacientes con diagnóstico de IC ambulatorios y dados de alta luego de una internación porIC aguda atendidos en dos centros. Se calcularon los puntajes 3C-HF y MAGGIC. Se evaluó como punto final la mortalidadglobal al año. La capacidad de discriminación de estos puntajes se analizó a partir del cálculo del área bajo la curva (ABC)ROC, y la calidad de su calibración, aplicando el test de Hosmer-Lemeshow. Se compararon ambas ABC mediante el test deHanley-Mc Neil.Resultados: Se incluyeron 704 pacientes con una edad promedio de 73 ± 11 años, el 39,6% eran mujeres. La mortalidad al añofue del 12,4% (n = 87). Ambos puntajes fueron predictores independientes de mortalidad, con HR de 1,03 (IC95% 1,008-1,06;p = 0,02) y 1,08 (IC95% 1,02-1,13; p = 0,004) para el puntaje 3C-HF y el MAGGIC, respectivamente. El 3C-HF presentó unABC de 0,70 (IC95% 0,64-0,75) y el MAGGIC de 0,67 (IC95% 0,61-0,73), sin diferencias entre las ABC (p = 0,41). Ambospresentaron adecuada calibración (p = 0,06 y p = 0,32, respectivamente).Conclusión: Los puntajes 3C-HF y MAGGIC fueron predictores de mortalidad a un año, con una moderada capacidad de discriminareventos y una adecuada calibración. No hubo diferencias en la capacidad de discriminación entre ambos puntajes

A phase II dose-escalation trial of perioperative desmopressin (1-desamino-8-d-arginine vasopressin) in breast cancer patients

Desmopressin (dDAVP) is a well-known peptide analog of the antidiuretic hormone vasopressin, used to prevent excessive bleeding during surgical procedures. dDAVP increases hemostatic mediators, such as the von Willebrand factor (vWF), recently considered a key element in resistance to metastasis. Studies in mouse models and veterinary trials in dogs with locally-advanced mammary tumors demonstrated that high doses of perioperative dDAVP inhibited lymph node and early blood-borne metastasis and significantly prolonged survival. We conducted a phase II dose-escalation trial in patients with breast cancer, administering a lyophilized formulation of dDAVP by intravenous infusion in saline, 30–60 min before and 24 h after surgical resection. Primary endpoints were safety and tolerability, as well as selection of the best dose for cancer surgery. Secondary endpoints included surgical bleeding, plasma levels of vWF, and circulating tumor cells (CTCs) as measured by quantitative PCR of cytokeratin-19 transcripts. Only 2 of a total of 20 patients experienced reversible adverse events, including hyponatremia (grade 4) and hypersensitivity reaction (grade 2). Reactions were adequately managed by slowing the infusion rate. A reduced intraoperative bleeding was noted with increasing doses of dDAVP. Treatment was associated with higher vWF plasma levels and a postoperative drop in CTC counts. At the highest dose level evaluated (2 μg/kg) dDAVP appeared safe when administered in two slow infusions of 1 μg/kg, before and after surgery. Clinical trials to establish the effectiveness of adjunctive perioperative dDAVP therapy are warranted. This trial is registered on www.clinicaltrials.gov (NCT01606072).Fil: Weinberg, Ruth S.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Grecco, Marcelo O.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Ferro, Gimena S.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Seigelshifer, Debora Judith. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Perroni, Nancy V.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Terrier, Francisco J.. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Maronna, Esteban. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Sánchez Marull, Ricardo. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Frahm, Isabel. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Guthmann, Marcelo D.. Laboratorio Elea; ArgentinaFil: Di Leo, Daniela. Laboratorio Elea; ArgentinaFil: Spitzer, Eduardo. Laboratorio Elea; ArgentinaFil: Ciccia, Graciela Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Pifano, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Torbidoni, Ana Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Ripoll, Giselle Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Roberto E.. Laboratorio Elea; ArgentinaFil: Demarco, Ignacio A.. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentin