Optimización del tratamiento de la anemia inducida por quimioterapia con Eritropoyetina Recombinante humana en el paciente con cáncer: Desarrollo de modelos predictivos de anemia y de respuesta a la Eritropoyetina.

RESUMEN Desarrollar y validar un modelo predictivo de anemia moderada-severa (AMS) (Hb < 10g/dL) en pacientes con tumores sólidos antes del inicio de la QT. Comparar la efectividad y el coste de dos pautas de Epoetin alfa: 10.000 UI sc tiw versus 40.000 UI sc qw en el tratamiento de la anemia inducida QT. Desarrollar un modelo predictivo de respuesta a la Eritropoyetina. MATERIAL Y MÉTODO Estudio de intervención cuasi experimental de cohortes prospectivo, abierto, multicéntrico, estratificado y controlado en pacientes con cáncer no hematológico que iban a iniciar tratamiento con QT y que presentaban una Hb basal > 10 g/dl. Los pacientes podían recibir epoetin alfa (10.000 UI sc tiw o 40.000 UI sc qw) para intentar mantener niveles de Hb en torno los 12 g/dL. Se recogieron al inicio y antes de cada ciclo características clínicas del paciente, del tumor, del tratamiento y parámetros de laboratorio. Analizamos todos los parámetros potencialmente relacionados con el desarrollo de anemia moderada-severa y los relacionados con la respuesta hematológica a la eritropoyetina mediante análisis multivariante con técnicas de regresión logística para desarrollar los modelos predictivos de anemia y respuesta. Para valorar el efecto del peso corporal en la eficacia de la dosis de epoetin alfa administrada, creamos la variable Razón de Infra-Sobredosificación (Razón ISD), definida como [Dosis semanal de epoetin administrada/Dosis teórica semanal ajustada al peso (450 UI/Kg.)] x 100. Fueron incluidos 599 pacientes, de los cuales 409 (69,4%) recibieron Epoetin alfa: 205 con una pauta de 10.000 UI sc tiw y 204 pacientes con 40.000 UI sc qwW. A pesar de no ser un estudio aleatorizado, no se observaron diferencias significativas en las características basales de los pacientes entre los dos grupos de tratamiento, excepto en el hierro plasmático y el Índice de Saturación de Transferina (IST). RESULTADOS Desarrollo y Validación de un Modelo de Riesgo de Anemia: Sólo seis variables se mostraron como factores de riesgo independientes de AMS: edad avanzada, estatura alta, la no cirugía previa del tumor primario, el número de transfusiones de hematíes previos, la QT basada en platinos y una Hb basal baja. A cada factor predictivo se le asignó un valor de riesgo en función del peso de su coeficiente β en el modelo, para construir un índice de riesgo de 0-11 puntos. Un índice de riesgo de 6 se identificó como el punto óptimo de corte que maximizaba la sensibilidad (69,4%) y la especificidad (92,8%) del modelo. El valor predictivo positivo (VPP) fue del 76,4% y el valor predictivo negativo (VPN) del 90,1. El AUC de la curva ROC fue 0,796 (IC 95%: 0,752-0,841). Para validar el modelo, las variables predictivas del modelo fueron aplicadas sobre una muestra aleatoria independiente (muestra de validación; n=104). El punto óptimo de corte del índice de riesgo (5), la sensibilidad (65,2%), la especificidad (92,1%), el VPP (71,4%) y el VPN (89,8%) fueron comparables a los valores de la población de la muestra de inferencia. Observamos una buena correlación directa entre la puntuación de riesgo, la probabilidad de anemia y el porcentaje de pacientes que desarrollaron AMS durante el estudio, dando soporte a su uso clínico. Comparación de la Eficacia de dos Pautas de Epoetin alfa: 10.000 UI tiw versus 40.000 UI qw. La Hb media al inicio del tratamiento con epoetin alfa fue similar en ambos grupos, 11,3 g/dL para la pauta 10.000 UI tiw versus 11,1 g/dL para la pauta 40.000 UI qw (p=0.139). Durante las 3 primeras semanas de tratamiento los niveles de hemoglobina se incrementaron en ambos grupos pero posteriormente iniciaron un descenso en el grupo 10.000 tiw hasta alcanzar niveles iniciales, mientras que el grupo con 40.000 qw mantuvo los niveles de Hb. El incremento máximo de Hb fue mayor en el grupo de 40.000 qw (1.6 g/dL; IC 95%: 1.4-1.7 g/dL) que en el grupo de 10.000 UI tiw (1.1 g/dL; IC 95%: 1.0-1.3 g/dL) (p=0.007); así como la Hb media durante el tratamiento, 11.4 g/dL (IC 95%: 11.2-11.6 g/dL) para el grupo tiw frente a 11.7 g/dL (IC 95%: 11.5-11.9 g/dL) para el grupo qw (p=0.08). La proporción de pacientes que consiguieron una respuesta hematológica fue similar en ambos grupos, 67,3% para la pauta tiw versus 71,5% para la pauta qw (p=0,361). La tasa global de transfusión fue baja (12,2% de los pacientes), siendo ligeramente superior en el grupo de 10.000 UI tiw (13.7%) respecto al grupo de 40.000 UI qw (10,7%), con un riesgo relativo de transfusión de 1, 37 (IC 95%: 0.77-2.40). El número de semanas de tratamiento con epoetin alfa fue significativamente mayor en el grupo de 10.000 tiw (7.2 sem; IC 95%: 6.6-7.7) que en el grupo de 40.000 qw (6.2 sem; IC 95%: 5.9-6.7) (p=0.016). El 36.1% de los pacientes tratados con 10.000 tiw precisó incrementar la dosis de epoetin alfa, frente al 12.3% de pacientes en el grupo de 40.000 UI qw (p<0.0001). Esto hizo que la dosis media total de epoetin alfa por paciente fuese un 4% mayor en el grupo tiw (275 x 103 UI; IC 95%: 247-302 x 103 UI) que en el grupo qw (265 x 103; IC 95%: 245-285 x 103 UI). Desarrollo de un Modelo Predictivo de Respuesta a la Eritropoyetina. Sólo 4 variables se mostraron como factores predictivos independientes de respuesta a la eritropoyetina: el sexo femenino (OR: 1.83; IC 95%: 1.10-3.35); una Razón de Infra-sobre dosificación ≥ 95% (OR: 3.61; IC 95%: 1.34-9.79); un nivel de Hb alto al inicio del tratamiento con Epoetin alfa (OR: 2.93; IC 95%: 2.15-3.99) y un incremento de Hb a las 3 semanas de tratamiento (OR: 2.92; IC 95%: 2.21-3.86). A cada factor predictivo de respuesta se le asignó un valor predictivo en función del peso de su coeficiente β en el modelo, para construir un índice predictivo de respuesta de 0-9 puntos. Una puntuación de 5 en el índice de riesgo fue identificado como el punto óptimo de corte que maximiza la sensibilidad (83,5%) y la especificidad (77,5%) del modelo. El valor predictivo positivo (VPP) fue del 89,2% y el valor predictivo negativo (VPN) del 67,5%. El AUC de la curva ROC fue 0,879 (IC 95%: 0,845-0,912). Observamos también una buena correlación directa entre la puntuación en el índice predictivo, la probabilidad de respuesta y el porcentaje de pacientes que responden al tratamiento con eritropoyetina. CONCLUSIONES Desarrollamos un modelo de riesgo de AMS con una exactitud diagnóstica y poder discriminativo satisfactorios que permite identificar los pacientes con alto riesgo antes de iniciar un tratamiento QT, permitiendo planificar el manejo de la anemia, bien intensificando el seguimiento de los síntomas y niveles de Hb o iniciando de forma temprana o precoz el tratamiento con eritropoyetinas, optimizando el manejo de estos pacientes. El modelo fue validado de forma satisfactoria en una muestra aleatoria independiente, lo que puede permitir su aplicación en la población general. Los resultados obtenidos pueden dar soporte a los datos publicados de que epoetin alfa es eficaz en el tratamiento de la anemia asociada al cáncer, tanto si se administra tres veces a la semana (tiw) como una vez a la semana (qw), siendo esta última pauta más cómoda para el paciente. No obstante, en nuestro estudio la pauta de epoetin alfa 40.000 UI qw se mostró ligeramente superior a la pauta de 10.000 UI tiw en mantener los niveles de Hb durante todo el tratamiento y sin un aumento en el gasto de unidades de epoetin alfa, efecto que mantuvo en todo el rango de peso de los pacientes y sin incrementar el coste. Desarrollamos un modelo predictivo de respuesta a la eritropoyetina con una exactitud diagnóstica y poder discriminativo también satisfactorios. Este modelo podría identificar pacientes con baja probabilidad de respuesta a la eritropoyetina, en quienes un aumento de la dosis ajustada al peso o el cese del tratamiento con eritropoyetina, podría optimizar el uso de estas moléculas. __________________________________________________________________________________________________OBJECTIVES To develop and validate a predictive risk model for moderate-to-severe anemia (MSA) in patients with solid tumors before chemotherapy was begun. To Evaluate the efficacy of two fixed dose of epoetin alpha, 10,000 IU three-times-weekly (tiw) versus 40,000 IU once-weekly (qw), in the management of Chemotherapy-induced anemia. To develop a model to predict haematopoietic response (HR) to Erythropoietin in anemic patients with solid tumors receiving chemotherapy (CT). PATIENTS AND METHODS We performed a quasi-experimental prospective, multicenter, open, controlled cohort study of patients with solid tumors receiving chemotherapy with or without concomitant radiotherapy and with a baseline Hb >10 g/dL. Patients received epoetin alpha (10,000 IU tiw or 40,000 IU qw) and oral iron supplements to maintain Hb level as close to 12 g/dL as possible, in accordance with clinical guidelines. Epoetin alpha dose could be increased to 60,000 IU qw depending on Hb response. The criteria for red blood cell transfusion were Hb <8 g/dL or poorly-tolerated anemia <10 g/dL. Patients demographics, clinical and tumor characteristics, laboratory parameters and CT agents were collected prospectively just before the administration of each course of CT. Multivariate logistic regression was used to identify independent risk factors for anemia and predictive factors for response to erythropoietin. These analyses were adjusted for confounding factors. An additive risk and predictive scoring system based on regression parameters was created, and a receiver operating characteristic (ROC) curve was plotted to measure predictive accuracy of the models. Moderate-to-severe anemia (MSA) was defined as a decrease in Hb below 10 g/dL during chemotherapy. Haematopoietic response was defined as an increase in Hb ≥ 2 g/dL or achievement of a Hb level ≥ 12 g/dL at any time point during the study. We prospectively included a total of 599 patients diagnosed with non-hematologic cancer who were scheduled to begin chemotherapy at two university hospitals in Valencia, Spain. To develop and validate the predictive model for anemia we divided the study population (N=599) randomly into two subsamples, one for model derivation (N=495) and one for validation (N=104). Mean baseline Hb was 13.2 g/dL (95% CI: 13.113.4 g/dL), and only 30.1% of the patients had anemia on inclusion. Concomitant radiotherapy was used in 21.4% of the patients. Treatment with epoetin alpha was used in 69.4% of the patients. Only 24.7% of patients developed MSA. About 19% of the patients needed at least one red blood cell transfusion. RESULTS Development and Validation of the Risk Model for Anemia Advanced age, higher stature, no previous surgery for a primary tumor, number of previous red cell transfusions, treatment with platinum-based chemotherapy, and low baseline hemoglobin were identified as independent predictors for moderate-to-severe anemia. A risk score of 6 was the optimal cut-off to maximize sensitivity (69.4%) and specificity (92.8%) of the prediction tool. Positive and negative predictive values were 76.4% and 90.1%, respectively. The ROC analysis of the derivation datasets had an area under the ROC curve of 0.79 (95% CI: 0.75-0.84). A ROC curve plotted for the validation sample and the total population yielded AUC values similar to those obtained for the derivation sample (0.791 and 0.795), which validated the accuracy of the risk model. Risk score, probability of anemia and percentage of patients expected to become anemic apparently correlated well. Comparing the Efficacy of Two fixed dose of Epoetin Alpha, 40,000 IU Once-Weekly (qw) versus 10,000 IU Three-Times-Weekly (tiw). 409 patients (64% males) were treated with epoetin: 205 patients received epoetin alpha 10,000 IU tiw and 204 patients received 40,000 IU qw. The overall response rate was 69.5%. There were no significant differences in the demographic and baseline clinical characteristics between the two treatment groups. Haematopoietic response rate was similar in both groups (67.3% for tiw versus 71.5% for qw; p=0.361). Mean Hb during epoetin treatment was similar too, 11.4 g/dL (95% CI 11.3-11.6) for tiw versus 11.6 g/dL (95% CI 11.4-11.8) for qw (p=0.176). The mean change in Hb was higher in qw cohort, 1.9 g/dL (95% CI 1.3-2.1) than in tiw cohort, 1.1 g/dL (95% CI 1.0-1.3) (p=0.007). Hemoglobin level at the end of study was 11.3 g/dL (95% CI 11.1-11.6) for tiw group versus 11.8 g/dL (95% CI 11.6-12.1) for qw group (p=0.007). Dose was increased in 36.1% of pts in tiw cohort versus 12.3% in qw cohort (p=0.0001). Mean number of weeks of epoetin treatment was 7.2 w (95% CI 6.6-7.8) for tiw group versus 6.2 w (95% CI 5.8-6.7) for qw (p=0,016). Mean weeks with escalating dose of epoetin was higher in tiw group (2.1 w; 95% CI 1.4-2.5) than in qw group (0.6 w; 95% CI 0.4-0.8) (p=0.0001). The rate of patients transfused was similar in both groups (13.7% for tiw vs 10.8% for qw; p=0.576). Development a Predictive Model of Response to Erythropoietin. Only four variables were independent predictive factors for haematopoietic response: gender female (OR: 1.92; 95%CI: 1.05-3.49); percentage of underdose of Epoetin alpha respected to theoretical weight-based dosing [weekly dose administered / (450 IU qw*weigh)] (OR: 3.18; 95%CI: 1.2-8.42); Hb level at the begin of Epo treatment (OR: 2.98; 95%CI: 2.2-4.03); change in Hb level after 3 weeks (OR: 2.96; 95%CI: 2.25-3.89). A statistical weight was assigned for each predictive factor on the basis of regression model beta coefficients to develop a predictive scoring system (0-9). The probability of HR was calculated over a range of total score. A risk score of 5 was identified as being the optimal cut-off to maximize sensitivity (83.5%) and specificity (77.5%). Positive and negative predictive values were 89.2% and 67.5% respectively. The ROC analysis obtained an area under the ROC curve of 0.879 (95%CI: 0.845-0.912). Predictive score, probability of response and percentage of patients who had a haematopoietic response apparently correlated well. CONCLUSIONS This risk model for anemia showed acceptable accuracy in correctly predicting which patients will become anemic in approximately 80% of the cases, and was validated in a random validation subsample. Risk score, probability of anemia, and the percentage of patients who become anemic appeared to correlate well, lending support to use of the model in clinical practice. This model can identify patients at high risk of anemia before chemotherapy is started, providing clinicians with an opportunity to plan appropriate, pro-active anemia management which will enhance patient care. Epoetin alpha is effective in the treatment of the chemotherapy-induced anemia, so much if it administered three times a week (tiw) like once a week (qw), being this last more comfortable rule for the patient. Dose of epoetin alpha 40.000 IU qw seems to have more efficacy that 10.000 IU tiw in maintaining and increasing Hb levels, but with a shorter duration of epoetin treatment and lower need of escalating dose and, probably, with a better cost-effectiveness. Also, dose of 40.000 UI qw maintained the clinical effectiveness in the whole range of the patients' weight and without increasing the cost. The predictive model for haematopoietic response showed too acceptable accuracy in correctly predicting which patients will response to erythropoietin in approximately 90% of the cases. Predictive score, probability of response and percentage of patients who had a haematopoietic response apparently correlated well, lending support to use in clinical practice. This model could be useful to identify patients at low probability of response to EPO, in whom the increase fixed dose of EPO adjusting to weight or the stop of EPO treatment, could optimize the use of these molecules

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

33 p.-9 fig.-2 tab. Muñoz-Felix. J. M. et al.Transforming growth factor beta 1 (TGF-β1) is one of the most studied cytokines involved in renal tubulo¬interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-β1 actions in different biological processes, includ¬ing ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG+) and we have performed an UUO in S-ENG+ and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG+ mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG+ mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain.This study has been supported by grants from Ministerio de Economía y Competitividad of Spain (SAF2013-43421-R to CB; and SAF2013-45784-R to JML-N), Junta de Castilla y León (GR100, JML-N), Institute Queen Sophie for Renal Research, Fundación Renal Íñigo Álvarez de Toledo, Madrid, Spain (0016¬002), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, CB) (ISCIII-CB06/07/0038) and Red de Investigación Cooperativa en Enfermedades Renales (REDINREN, JML-N) (R12/0021/ 0032). CIBERER and REDINREN are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds. BO and ENG are supported by fellowships from Ministerio de Economía y Competitividad (BES-2011-048968 and BES-2008-005550). JMMF, LPR and CC are supported by fellowships from Junta de Castilla y León and Fondo Social Europeo (EDU/1204/2010 and EDU/1083/2013).Peer reviewe

Producción de ovino de carne en medio semiárido

Unpublishe

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

In vitro and in vivo effects of an anti-mouse endoglin (CD105)-immunotoxin on the early stages of mouse B16MEL4A5 melanoma tumours

11 p.-6 fig.TGF-beta superfamily co-receptors are emerging as targets for cancer therapy, acting both directly on cells and indirectly on the tumour neovasculature. Endoglin (CD105), an accessory component of the TGF-beta receptor complex, is expressed in certain melanoma cell lines and the endothelial cells of tumour neovessels. Targeting endoglin with immunotoxins is an attractive approach for actively suppressing the blood supply to tumours. Here, we report evidence indicating that endoglin is expressed in mouse melanoma B16MEL4A5 and mouse fibroblast L929 cell lines. We prepared an immunotoxin to target endoglin by coupling the rat anti-mouse MJ7/18 (IgG2a) monoclonal antibody (mAb) to the non-toxic type 2 ribosome-inactivating protein nigrin b (Ngb) with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) as a linker with a molar nigrin b at a MJ7/18 stoichiometry of 2:1. The MJ7-Ngb immunotoxin generated killed both cell lines, with IC50 values of 4.2 × 10−9 M for B16MEL4A5 and 7.7 × 10−11 M for L929 cells. For in vivo assays of the immunotoxin, B16MEL4A5 cells were injected subcutaneously into the right flanks of 6-week-old C57BL/6 J mice. When the animals developed palpable solid tumours, they were subjected to treatment with the immunotoxin. While treatment with either MJ7/18 mAb or Ngb did not affect tumour development, treatment with the immunotoxin completely and steadily blocked tumour growth up to 7 days, after which some tumours re-grew. Thus, vascular-targeting therapy with this anti-vascular immunotoxin could promote the destruction of newly created tumour vessels at early stages of B16MEL4A5 tumour development and readily accessible CD105+ B16MEL4A5 melanoma cells.This research was supported by grants from the Junta de Castilla y León (Grupo de Excelencia GR106 and Convenio-Consejería de Sanidad) and UVA-GIR funding to T.G., Fondo de Investigaciones Sanitarias FISPI02/0917 to R.M. and FISPI04/1279 to J.M.F., Ministerio de Ciencia e Innovación of Spain (SAF2010-19222 to C.B.) and Genoma España (MEICA) to C.B.Peer reviewe