Immunogenicity of COVID-19 vaccines in lung cancer patients.

OBJECTIVE: Patients with lung cancer are at increased risk of SARS-CoV-2 infection and severe complications from COVID-19, but information on the efficacy of anti-SARS-CoV-2 vaccine in these patients is scarce. We aimed at evaluating the safety and immunogenicity of COVID-19 vaccines in this population. PATIENTS AND METHODS: The prospective, nationwide SOLID substudy, enrolled adults with lung cancer who were fully vaccinated against COVID-19. Serum anti-SARS-CoV-2 IgG antibody levels were quantitatively assessed two weeks and six months after receipt of the last dose using a chemiluminescent microparticle immunoassay. Multivariate odds ratios for the association between demographic and clinical factors and seronegativity after vaccination were estimated. RESULTS: 1973 lung cancer patients were enrolled. Most patients had stage IV disease (66%) and were receiving active cancer treatment (82.7%). No significant differences were found in the probability of being seronegative for anti-SARS-CoV-2 IgG antibodies after full vaccination between patients who were receiving active cancer treatment and those who were not (p = 0.396). The administration of immunotherapy or oral targeted therapy and immunization with mRNA-1273 COVID-19 vaccine were factors independently associated with increased odds of being seropositive after vaccination. From all patients, 1405 received the second dose of vaccine and high levels of antibody titers were observed in 93.6% of patients two weeks after second dose. At six months, multivariate logistic regression analysis showed that performance status ≥ 2 was independently associated with a higher probability of being seronegative after full vaccination with an OR 4.15. On the other hand, received chemotherapy or oral target therapy and vaccination with mRNA-1273 were a factor independently associated with lower odds of being seronegative after full vaccination with an OR 0.52, 0.37 and 0.34, respectively. CONCLUSIONS: Lung cancer patients can safely achieve a strong immune response against SARS-CoV-2 after full vaccination, regardless of the cancer treatment received. TRIAL REGISTRATION: NCT04407143.

Prevalence of thrombosis in patients with cancer and SARS-CoV-2 infection.

Background: Covid-19 infection and cancer are associated with an increased risk of thrombotic events. The aim of our study is to analyze the cumulative incidence of thrombosis in oncological patients with Covid-19 and detect differences with the non-cancer Covid-19 population. Methods: We retrospectively reviewed 1127 medical records of all admitted patients to ward of the Hospital Universitario Infanta Leonor (Madrid, Spain), including 86 patients with active cancer between March 5th, 2020 to May 3rd, 2020. We analyzed cumulative incidence of thrombosis and risk factors associated to the cancer patient's cohort. Results: We diagnosed 10 thrombotic events in 8 oncological patients with a cumulative incidence of 9.3%. A statistically significant association was found regarding thrombosis and history of obesity (p = 0.009). No differences related to cumulative incidence of thrombosis between both groups were detected (9.8% vs 5.80%) in our hospital (p = 0.25). Conclusion: No significant differences were observed in the cumulative incidence of thrombosis in the two study groups. The thrombotic effect of Covid-19 is not as evident in cancer patients and does not seem to be added to its prothrombotic activity.

Antecedentes: La infección por COVID-19 y el cáncer se asocian a mayor riesgo de eventos trombóticos. El objetivo de nuestro estudio es analizar la incidencia acumulada de trombosis en pacientes oncológicos con COVID-19 y detectar diferencias con la población sin cáncer y COVID-19. Métodos: Revisamos retrospectivamente 1.127 historias clínicas de los pacientes ingresados en del Hospital Infanta Leonor (Madrid, España), incluyendo 86 pacientes con cáncer activo entre el 5 de marzo y el 3 de mayo de 2020. Se analizó la incidencia acumulada de trombosis y los factores de riesgo asociados a la cohorte de pacientes con cáncer. Resultados: Diagnosticamos 10 eventos trombóticos en 8 pacientes oncológicos, con una incidencia acumulada del 9,3%. Se encontró una asociación estadísticamente significativa entre trombosis y obesidad (p = 0,009). No se detectaron diferencias relacionadas con la incidencia acumulada de trombosis entre ambos grupos (9,8%vs. 5,80%, p = 0,25). Conclusión: No se observaron diferencias significativas en la incidencia acumulada de trombosis en los 2 grupos de estudio. El efecto trombótico de la COVID-19 no es tan evidente en los pacientes con cáncer y no parece sumarse a su actividad protrombótica.

Prevalence of thrombosis in patients with cancer and SARS-CoV-2 infection

Background: Covid-19 infection and cancer are associated with an increased risk of thrombotic events. The aim of our study is to analyze the cumulative incidence of thrombosis in oncological patients with Covid-19 and detect differences with the non-cancer Covid-19 population.MethodsWe retrospectively reviewed 1127 medical records of all admitted patients to ward of the Hospital Universitario Infanta Leonor (Madrid, Spain), including 86 patients with active cancer between March 5th, 2020 to May 3rd, 2020. We analyzed cumulative incidence of thrombosis and risk factors associated to the cancer patient's cohort.ResultsWe diagnosed 10 thrombotic events in 8 oncological patients with a cumulative incidence of 9.3%. A statistically significant association was found regarding thrombosis and history of obesity (p=0.009). No differences related to cumulative incidence of thrombosis between both groups were detected (9.8% vs 5.80%) in our hospital (p=0.25).ConclusionNo significant differences were observed in the cumulative incidence of thrombosis in the two study groups. The thrombotic effect of Covid-19 is not as evident in cancer patients and does not seem to be added to its prothrombotic activity. (AU)

Antecedentes: La infección por COVID-19 y el cáncer se asocian a mayor riesgo de eventos trombóticos. El objetivo de nuestro estudio es analizar la incidencia acumulada de trombosis en pacientes oncológicos con COVID-19 y detectar diferencias con la población sin cáncer y COVID-19.MétodosRevisamos retrospectivamente 1.127 historias clínicas de los pacientes ingresados en del Hospital Infanta Leonor (Madrid, España), incluyendo 86 pacientes con cáncer activo entre el 5 de marzo y el 3 de mayo de 2020. Se analizó la incidencia acumulada de trombosis y los factores de riesgo asociados a la cohorte de pacientes con cáncer.ResultadosDiagnosticamos 10 eventos trombóticos en 8 pacientes oncológicos, con una incidencia acumulada del 9,3%. Se encontró una asociación estadísticamente significativa entre trombosis y obesidad (p=0,009). No se detectaron diferencias relacionadas con la incidencia acumulada de trombosis entre ambos grupos (9,8%vs. 5,80%, p=0,25).ConclusiónNo se observaron diferencias significativas en la incidencia acumulada de trombosis en los 2 grupos de estudio. El efecto trombótico de la COVID-19 no es tan evidente en los pacientes con cáncer y no parece sumarse a su actividad protrombótica. (AU)

Seroprevalence and immunological memory against SARS-CoV-2 in lung cancer patients: the SOLID study.

BACKGROUND: At present, we did not find any articles that studied seroprevalence and its persistence several months later in lung cancer patients in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with coronavirus disease 2019 (COVID-19) go on to develop antibodies (Abs) against viral proteins. However, it is not known how long these Abs last nor whether cancer treatments could affect the duration of immune response. METHODS: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 infection was carried out in 50 Spanish hospitals. Eligibility criterion was the diagnosis of any lung cancer. The determination of anti-SARS-CoV-2 IgG Abs was performed by qualitative immuno-enzymatic assay using enzyme-linked immunosorbent assay (ELISA) kit from NovaLisa whose Abs target the recombinant antigen N of the nucleocapsid of SARS-CoV-2. The first Ab determination was performed between April 21 and June 3, 2020. The second Ab determination was performed in all previously seropositive patients, between September 10 and November 20, 2020. Study objectives were to prospectively determine seroprevalence in unselected lung cancer patients during the first wave of the pandemic; the persistence of immunity; protection or lack thereof against reinfection; and the influence of treatments on maintenance or loss of immunity. RESULTS: Of 1,500 patients, 128 were seropositive, overall prevalence of 8.5% seropositivity [95% confidence interval (CI): 7.2-10.1%]. Seventy-five percent were in active cancer treatment. Forty-seven point seven percent of IgG positive participants had experienced a symptomatic illness suspected of being infected with SARS-CoV-2 (95% CI: 38.8-56.6%). A second determination was performed on average 4.5 months later [interquartile range (IQR), 4.0-5.0 months] and obtained for 104 of the initially seropositive patients (81%), it could not be obtained in 24 patients, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% of patients. The severity of the infection, the need for hospitalization (P=0.032) and the presence of symptoms at diagnosis (P=0.02) were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Abs loss. CONCLUSIONS: Immunity against SARS-CoV-2 does not appear to be compromised by treatment and persists beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04407143.

Prevalence of thrombosis in patients with cancer and SARS-CoV-2 infection.

BACKGROUND: Covid-19 infection and cancer are associated with an increased risk of thrombotic events. The aim of our study is to analyze the cumulative incidence of thrombosis in oncological patients with Covid-19 and detect differences with the non-cancer Covid-19 population. METHODS: We retrospectively reviewed 1127 medical records of all admitted patients to ward of the Hospital Universitario Infanta Leonor (Madrid, Spain), including 86 patients with active cancer between March 5th, 2020 to May 3rd, 2020. We analyzed cumulative incidence of thrombosis and risk factors associated to the cancer patient's cohort. RESULTS: We diagnosed 10 thrombotic events in 8 oncological patients with a cumulative incidence of 9.3%. A statistically significant association was found regarding thrombosis and history of obesity (p=0.009). No differences related to cumulative incidence of thrombosis between both groups were detected (9.8% vs 5.80%) in our hospital (p=0.25). CONCLUSION: No significant differences were observed in the cumulative incidence of thrombosis in the two study groups. The thrombotic effect of Covid-19 is not as evident in cancer patients and does not seem to be added to its prothrombotic activity.

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study.

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086-2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110-2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531-13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

Opioid-Induced Constipation in Oncological Patients: New Strategies of Management.

OPINION STATEMENT: Cancer-associated pain has traditionally been treated with opioid analgesics, often in escalating doses. Opioid-induced constipation (OIC) is a common problem associated with chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific action and do not target underlying mechanisms of OIC. This article will review prevalent, clinical presentation and recommendations for the treatment of OIC. An independent literature search was carried out by the authors. We reviewed the literature for randomized controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more effective assessment and management of OIC. Finally, traditional recommended therapies are appraised and compared with the latest pharmacological developments. Future research should address whether naloxegol is more efficacious by its comparison directly with first-line treatments, including laxatives.

Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials / Riesgo de tromboembolismo con agonistas del receptor de la trombopoyetina en pacientes adultos con trombocitopenia: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados y controlados

Background and objective: Romiplostim and eltrombopag are thrombopoietin receptor (TPOr) agonists that promote megakaryocyte differentiation, proliferation and platelet production. In 2012, a systematic review and meta-analysis reported a non-statistically significant increased risk of thromboembolic events for these drugs, but analyses were limited by lack of statistical power. Our objective was to update the 2012 meta-analysis examining whether TPOr agonists affect thromboembolism occurrence in adult thrombocytopenic patients. Materials and methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Updated searches were conduced on PubMed, Cochrane Central, and publicly available registries (up to December 2014). RCTs using romiplostim or eltrombopag in at least one group were included. Relative risks (RR), absolute risk ratios (ARR) and number needed to harm (NNH) were estimated. Heterogeneity was analyzed using Cochran's Q test and I2 statistic. Results: Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95–4.61%) for TPOr agonists and 1.46% (95% CI: 0.89–2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04–3.14) and an ARR of 2.10% (95% CI: 0.03–3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p = 0.43; I2 = 1.60%). Conclusions: Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect (AU)

Fundamento y objetivo: Los agonistas del receptor de la trombopoyetina (TPOr) (romiplostim y eltrombopag) promueven la diferenciación megacariocítica, la proliferación y la producción de plaquetas. En 2012, una revisión sistemática y metaanálisis informó de un aumento no estadísticamente significativo del riesgo tromboembólico para estos medicamentos, pero los análisis presentaban limitaciones por la falta de potencia estadística. El objetivo es actualizar el metaanálisis de 2012 examinando si los agonistas del TPOr afectan a la incidencia de tromboembolismos en los pacientes adultos con trombocitopenia. Material y métodos: Se llevó a cabo una revisión sistemática y metaanálisis de ensayos clínicos aleatorizados y controlados (ECA). Se actualizaron búsquedas llevadas a cabo en PubMed, Cochrane Central, y registros públicos (hasta Diciembre de 2014). Se incluyeron ECA en los que se administrara romiplostim o eltrombopag en al menos uno de los grupos de pacientes tratados. Se calcularon los riesgos relativos (RR), la diferencia absoluta de riesgo (ARR, por sus siglas en inglés) y el número necesario de pacientes para dañar (NNH). Se examinó la heterogeneidad estadística mediante la Q de Cochran y el estadístico I2. Resultados: Se incluyeron 15 estudios con 3026 pacientes adultos diagnosticados de trombocitopenia. Las frecuencias de acontecimientos tromboembólicos fueron de 3.69% ([intervalo de confianza] IC del 95%: 2,95–4,61%) para los agonistas del TPOr y de 1,46% (IC95%: 0,89–2,40%) para los controles. Los agonistas del TPOr se asociaron con un riesgo relativo de tromboembolismo de 1,81 (IC95%: 1,04–3,14) y una ARR del 2,10% (IC95%: 0,03–3,90%), que significa un NNH de 48. En general, no se encontró evidencia de heterogeneidad estadística (p = 0,43; I2 = 1,60%). Conclusiones: El metaanálisis actualizado sugiere que los agonistas del TPOr están asociados con un mayor riesgo de eventos thromboembólicos en comparación con los controles. Estos resultados apoyan las precauciones incluidas en la información del medicamento en la Unión Europea en relación con el riesgo tromboembólico (AU)

Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: Romiplostim and eltrombopag are thrombopoietin receptor (TPOr) agonists that promote megakaryocyte differentiation, proliferation and platelet production. In 2012, a systematic review and meta-analysis reported a non-statistically significant increased risk of thromboembolic events for these drugs, but analyses were limited by lack of statistical power. Our objective was to update the 2012 meta-analysis examining whether TPOr agonists affect thromboembolism occurrence in adult thrombocytopenic patients. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Updated searches were conduced on PubMed, Cochrane Central, and publicly available registries (up to December 2014). RCTs using romiplostim or eltrombopag in at least one group were included. Relative risks (RR), absolute risk ratios (ARR) and number needed to harm (NNH) were estimated. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic. RESULTS: Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95-4.61%) for TPOr agonists and 1.46% (95% CI: 0.89-2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04-3.14) and an ARR of 2.10% (95% CI: 0.03-3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p=0.43; I(2)=1.60%). CONCLUSIONS: Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect.

Identification of E545k mutation in plasma from a PIK3CA wild-type metastatic breast cancer patient by array-based digital polymerase chain reaction: Circulating-free DNA a powerful tool for biomarker testing in advance disease.

PIK3CA gene is frequently mutated in patients with breast cancer and it has been the focus of intense research. Inhibitors of PI3K pathway are being evaluated in ongoing clinical trials but the impact of PIKC3A mutation status on tumor response is yet uncertain. In the metastatic setting, several studies are evaluating the predictive value of PIK3CA mutations. However, results could be biased by biopsy localization. Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood and can potentially overcome such situation. As a proof of the concept, we present the case of a metastatic patient with a PIK3CA wild-type primary tumor in which the PIK3CA E545K mutation was identified in both the circulating-free DNA obtained from a peripheral blood sample and in the formalin-fixed, paraffin-embedded liver metastasis.

[Risks of dual blockade of the renin-angiotensin system compared with monotherapy: a systematic review and cumulative meta-analysis of randomized trials and observational studies]. / Bloqueo dual del sistema renina-angiotensina frente a la monoterapia: revisión sistemática y metaanálisis acumulativo de ensayos clínicos y estudios observacionales.

BACKGROUND: Previous work has suggested that dual blockade using inhibitors of the renin-angiotensin system (RAS) would be associated with an increase in side effects compared to monotherapy. We reexamined the safety of dual RAS blockade, especially in patients at risk, and explored the stability of the evidence accumulated over the years. METHOD: Systematic review with random-effects meta-analyses. We reviewed 15 previously published meta-analyses as the starting point. PubMed/Medline was searched for recent evidence from both observational and randomized controlled trials. Outcomes measures were: mortality (overall and cardiovascular), hyperkalemia, hypotension, renal failure, stroke, and treatment withdrawal due to adverse effects. We calculated relative risks (RR) and confidence intervals (95% CI) RESULTS: Dual RAS blockade was not associated with reduced relative risk (RR) overall mortality (RR:1.00, 0.96-1.05; 21 studies), cardiovascular mortality (RR:1.01, 0.94-1.09; 13 studies) or stroke (RR:1.02; 0.94-1.11; 11 studies) compared to monotherapy. Dual blockade was associated with an increased risk of hyperkalemia (RR:1.58, 1.37-1.81; 34 studies), hypotension (RR:1.66; 1.41-1.95; 25 studies), renal failure (RR:1.52;1.28-1.81; 29 studies) and treatment discontinuation due to adverse events (RR:1.26;1.22-1.30; 37 studies). These results were consistent in cohorts of patients with diabetes mellitus, kidney disease or heart failure. CONCLUSIONS: Dual RAS blockade increased (vs monotherapy) the risks of hyperkalemia, hypotension, renal failure and treatment discontinuation. Dual RAS blockade did not offer additional benefit in reducing overall mortality, cardiovascular mortality or stroke. These findings are consistent over time.

Bloqueo dual del sistema renina-angiotensina frente a la monoterapia: revisión sistemática y metaanálisis acumulativo de ensayos clínicos y estudios observacionales / Risks of dual blockade of the renin-angiotensin system compared with, mnotherapy: a systematic review and cumulative meta-analysis of randomized trials and observational studies

Fundamentos: Trabajos previos han sugerido que el bloqueo dual con inhibidores del sistema renina-angiotensina (SRA) estaría asociado a un incremento de efectos adversos comparado con la monoterapia. Se reexamina la seguridad del doble bloqueo del SRA, especialmente en pacientes de riesgo y se explora la estabilidad de la evidencia acumulada a lo largo de los años. Método: Revisión sistemática con metaanálisis de efectos aleatorios. Se revisaron 15 metaanálisis publicados anteriormente como punto de partida. Se realizó una búsqueda en PubMed/Medline de estudios observacionales y de ensayos clínicos controlados recientes. Las variables dependientes estudiadas fueron: mortalidad (general y cardiovascular), hiperpotasemia, hipotensión, insuficiencia renal, accidente cerebrovascular y la retirada del tratamiento por efectos adversos. Se calcularon los riesgos relativos (RR) y su intervalo de confianza (IC95%) Resultados: El bloqueo dual del SRA no se asoció con una reducción del RR de la mortalidad general (RR:1,00; IC95%: 0,96-1,05; 21 estudios), ni de la mortalidad cardiovascular (RR:1,01; 0,94-1,09; 13 estudios) ni del riesgo de accidente cerebrovascular (RR:1,02; 0,94-1,11; 11 estudios) en comparación con la monoterapia. El bloqueo dual se asoció a un riesgo aumentado de hiperpotasemia (RR:1,58; 1,37-1,81; 34 estudios), hipotensión (RR:1,66; 1,41-1,95; 25 estudios), daño renal (1,52; 1,28-1,81; 29 estudios) y retirada del tratamiento por efectos adversos (RR:1,26; 1,22-1,30; 37 estudios). Los resultados fueron consistentes en las cohortes de pacientes con diabetes mellitus, enfermedad renal o insuficiencia cardiaca. Conclusiones: El bloqueo dual del SRA vs monoterapia incrementa los riesgos de hiperpotasemia, hipotensión, insuficiencia renal e interrupción del tratamiento por efectos adversos. Además no ofrece beneficios adicionales por reducción de la mortalidad general, mortalidad cardiovascular o accidente cerebrovascular. Estos hallazgos son consistentes a lo largo del tiempo (AU)

Background: Previous work has suggested that dual blockade using inhibitors of the renin-angiotensin system (RAS) would be associated with an increase in side effects compared to monotherapy. We reexamined the safety of dual RAS blockade, especially in patients at risk, and explored the stability of the evidence accumulated over the years. Method: Systematic review with random-effects meta-analyses. We reviewed 15 previously published meta-analyses as the starting point. PubMed/Medline was searched for recent evidence from both observational and randomized controlled trials. Outcomes measures were: mortality (overall and cardiovascular), hyperkalemia, hypotension, renal failure, stroke, and treatment withdrawal due to adverse effects. We calculated relative risks (RR) and confidence intervals (95% CI) Results:Dual RAS blockade was not associated with reduced relative risk (RR) overall mortality (RR:1.00, 0.96-1.05; 21 studies), cardiovascular mortality (RR:1.01, 0.94-1.09; 13 studies) or stroke (RR:1.02; 0.94-1.11; 11 studies) compared to monotherapy. Dual blockade was associated with an increased risk of hyperkalemia (RR:1.58, 1.37-1.81; 34 studies), hypotension (RR:1.66; 1.41-1.95; 25 studies), renal failure (RR:1.52;1.28-1.81; 29 studies) and treatment discontinuation due to adverse events (RR:1.26;1.22-1.30; 37 studies). These results were consistent in cohorts of patients with diabetes mellitus, kidney disease or heart failure. Conclusions: Dual RAS blockade increased (vs monotherapy) the risks of hyperkalemia, hypotension, renal failure and treatment discontinuation. Dual RAS blockade did not offer additional benefit in reducing overall mortality, cardiovascular mortality or stroke. These findings are consistent over time (AU)

Riesgo tromboembólico con agonistas del receptor de la trombopoyetina en pacientes adultos con trombocitopenia: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados y controlados / Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials

Fundamento y objetivo: Los agonistas del receptor de trombopoyetina (TPOr) (romiplostim y eltrombopag) son un nuevo enfoque para el tratamiento de la trombocitopenia asociada a algunas enfermedades. Los agonistas del TPOr promueven la diferenciación megacariocítica, la proliferación y la producción de plaquetas. En la Unión Europea, han sido autorizados como medicamentos huérfanos, con una indicación restringida a los pacientes esplenectomizados con púrpura trombocitopénica inmune que son refractarios a otros tratamientos. Debido al incremento de los recuentos de plaquetas, estos fármacos pueden representar un riesgo de tromboembolias. Se analiza si los agonistas del TPOr afectan a la incidencia de acontecimientos tromboembólicos en pacientes adultos con trombocitopenia. Material y métodos: Revisión sistemática y meta-análisis de ensayos clínicos aleatorizados y controlados (ECA). Se realizó una búsqueda en PubMed, SCOPUS, Cochrane Central Register, web de las agencias reguladoras y registros de acceso público (p.ej, gubernamentales y de los fabricantes). Se incluyeron ECA en los que se administrara romiplostim o eltrombopag en al menos uno de los grupos de pacientes tratados. Se calcularon la reducción absoluta de riesgo (RAR), el número necesario de pacientes a dañar (NNH) y el riesgo relativo (RR). Se examinó la heterogenidad mediante la Q de Cochrane y el estadístico I2. Resultados: De las 373 publicaciones identificadas, 8 estudios cumplieron los criterios de inclusión (n=1.180 pacientes). Se encontraron variaciones en la calidad de la información entre estudios. Las frecuencias de acontecimientos tromboembólicos fueron de 3,1% [intervalo de confianza (IC) del 95% = 1,8-4,4%] para los agonistas del TPOr y de 1,7% (IC95% = 0,3-3,1%) para el grupo control (AU)

Background and objective: Thrombopoietin receptor (TPOr) agonists (romiplostim and eltrombopag) are a new approach for the treatment of thrombocytopenia-associated conditions. They promote megakaryocyte differentiation, proliferation and platelet production. In the European Union, both are orphan drugs with an indication restricted to splenectomized immune thrombocytopenic purpura patients who are refractory to other treatments. Due to increasing platelet counts, these drugs may represent a risk for thromboembolic complications. We analyzed whether TPOr agonists affect thromboembolisms occurrence in adult thrombocytopenic patients. Materials and methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Searches were carried out in PubMed, SCOPUS, Cochrane Central Register, regulatory agencies websites and publicly available registries of manufacturers. RCTs using romiplostim or eltrombopag in at least one group were included. Absolute risk ratios (ARR), number needed to harm (NNH) and relative risks (RR) were provided. Heterogeneity was analyzed using Cochran's Q test and I2 statistic. Results: Of 373 publications identified, 8 studies met the inclusion criteria (n=1180 patients). The quality of reporting amongst studies was variable. Estimated frequency of thromboembolisms was 3.1% (95% CI, 1.8-4.4%) for TPOr agonists and 1.7% (95% CI, 0.3-3.1%) for controls. Summary analyses produced overall meta-ARR for thromboembolisms of 1.8% (95% CI, −0.1-3.6%), and meta-RR of 1.5 (95% CI, 0.7-3.3), meaning a NNH of 55 (1 additional thromboembolism for each 55 patients treated with TPOr agonists). All pooled estimates were homogeneous (AU)

Uso de olmesartán en la prevención o retraso de la nefropatía diabética: algunas consideraciones / Olmesartan for the prevention or delay of diabetic nephropathy: some considerations

No disponible

Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: Thrombopoietin receptor (TPOr) agonists (romiplostim and eltrombopag) are a new approach for the treatment of thrombocytopenia-associated conditions. They promote megakaryocyte differentiation, proliferation and platelet production. In the European Union, both are orphan drugs with an indication restricted to splenectomized immune thrombocytopenic purpura patients who are refractory to other treatments. Due to increasing platelet counts, these drugs may represent a risk for thromboembolic complications. We analyzed whether TPOr agonists affect thromboembolisms occurrence in adult thrombocytopenic patients. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Searches were carried out in PubMed, SCOPUS, Cochrane Central Register, regulatory agencies websites and publicly available registries of manufacturers. RCTs using romiplostim or eltrombopag in at least one group were included. Absolute risk ratios (ARR), number needed to harm (NNH) and relative risks (RR) were provided. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic. RESULTS: Of 373 publications identified, 8 studies met the inclusion criteria (n=1180 patients). The quality of reporting amongst studies was variable. Estimated frequency of thromboembolisms was 3.1% (95% CI, 1.8-4.4%) for TPOr agonists and 1.7% (95% CI, 0.3-3.1%) for controls. Summary analyses produced overall meta-ARR for thromboembolisms of 1.8% (95% CI, -0.1-3.6%), and meta-RR of 1.5 (95% CI, 0.7-3.3), meaning a NNH of 55 (1 additional thromboembolism for each 55 patients treated with TPOr agonists). All pooled estimates were homogeneous. CONCLUSIONS: TPOr agonists show a numerically but non-statistically significant trend to increase the occurrence of thromboembolisms compared to controls, but analyses were underpowered and in some studies information on outcomes was incomplete and of poor quality.

Intraorganellar acidification by V-ATPases: a target in cell proliferation and cancer therapy.

Vacuolar-type ATPases are multicomponent proton pumps involved in the acidification of single membrane intracellular compartments such as endosomes and lysosomes. They couple the hydrolysis of ATP to the translocation of one to two protons across the membrane. Acidification of the lumen of single membrane organelles is a necessary factor for the correct traffic of membranes and cargo to and from the different internal compartments of a cell. Also, V-ATPases are involved in regulation of pH at the cytosol and, possibly, extracellular milieu. The inhibition of V-ATPases has been shown to induce apoptosis and cell cycle arrest in tumour cells and, therefore, chemicals that behave as inhibitors of this kind of proton pumps have been proposed as putative treatment agents against cancer and many have been patented as such. The compounds filed in patents fall into five major types: plecomacrolides, benzolactone enamides, archazolids, chondropsins and indoles. All these have proved to be apoptosis inducers in cell culture and many to be able to reduce xenograft tumor growth in murine models. The present review will summarize their general structure, origin and mechanisms of action and put them in relation to the patents registered so far for the treatment of cancer.

Chlamydomonas CONSTANS and the evolution of plant photoperiodic signaling.

BACKGROUND: The circadian clock controls several important processes in plant development, including the phase transition from vegetative growth to flowering. In Arabidopsis thaliana, the circadian-regulated gene CONSTANS (CO) plays a central role in the photoperiodic control of the floral transition, one of the most conserved flowering responses among distantly related plants. CO is a member of a plant-specific family of transcription factors, and when it arose during the evolution of higher plants is unclear. RESULTS: A CO homologous gene present in the genome of the unicellular green alga Chlamydomonas reinhardtii (CrCO) can complement the Arabidopsis co mutation and promote early flowering in wild-type plants when expressed under different promoters. Transcript levels of FLOWERING LOCUS T (FT), the main target of CO, are increased in CrCO transgenic plants in a way similar to those in plants overexpressing CO. In the microalga, expression of CrCO is influenced by day length and the circadian clock, being higher in short photoperiods. Reduction of CrCO expression in Chlamydomonas by RNA interference induces defects in culture growth, whereas algae induced to express high levels of CrCO show alterations in several circadian output processes, such as starch accumulation and the onset of expression of genes that regulate the cell cycle. CONCLUSIONS: The effects observed may reflect a conserved role for CrCO in the coordination of processes regulated by photoperiod and the circadian clock. Our data indicate that CO orthologs probably represent ancient regulators of photoperiod-dependent events and that these regulators arose early in the evolutionary lineage that gave rise to flowering plants.