Temocillin versus meropenem for the targeted treatment of bacteraemia due to third-generation cephalosporin-resistant Enterobacterales (ASTARTÉ): protocol for a randomised, pragmatic trial.

INTRODUCTION: Alternatives to carbapenems are needed in the treatment of third-generation cephalosporin-resistant Enterobacterales (3GCR-E). Temocillin is a suitable candidate, but comparative randomised studies are lacking. The objective is to investigate if temocillin is non-inferior to carbapenems in the targeted treatment of bacteraemia due to 3GCR-E. METHODS AND ANALYSIS: Multicentre, open-label, randomised, controlled, pragmatic phase 3 trial. Patients with bacteraemia due to 3GCR-E will be randomised to receive intravenously temocillin (2 g three times a day) or carbapenem (meropenem 1 g three times a day or ertapenem 1 g once daily). The primary endpoint will be clinical success 7-10 days after end of treatment with no recurrence or death at day 28. Adverse events will be collected; serum levels of temocillin will be investigated in a subset of patients. For a 10% non-inferiority margin, 334 patients will be included (167 in each study arm). For the primary analysis, the absolute difference with one-sided 95% CI in the proportion of patients reaching the primary endpoint will be compared in the modified intention-to-treat population. ETHICS AND DISSEMINATION: The study started after approval of the Spanish Regulatory Agency and the reference institutional review board. Data will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04478721.

Incidencia y supervivencia de los tumores de novo en el trasplante hepático / Incidence and survival rate of de novo tumors in liver transplants

INTRODUCCIÓN: La mayor supervivencia del paciente trasplantado viene acompañada del aumento en la tasa de tumores de novo (TN) que representan la complicación tardía más frecuente. Podemos distinguir entre tumores de piel no melanoma (TPNM), síndrome linfoproliferativo postrasplante (SLPT) y tumores de órgano sólido (TOS). Nuestro objetivo es determinar la incidencia de los distintos TN, el tiempo trascurrido hasta su diagnóstico y su supervivencia en nuestro medio. MATERIAL Y MÉTODO: Realizamos un estudio retrospectivo de 1.071 trasplantados hepáticos desde 1990 hasta 2015 en nuestro centro. Analizamos las variables demográficas, la incidencia de TN y la supervivencia. RESULTADOS: Se desarrollaron 184 TN en 1.071 pacientes trasplantados (17%), en el 19% de los varones y en el 13% de las mujeres (p = 0,004). Los TN más frecuentes fueron los TPNM (29%), pulmón (18%), cabeza y cuello (16%), SLPT (10%) y gastrointestinales (8%). La mediana del tiempo de diagnóstico fue de 7,9 años en los TPNM, 3,9 años en SLPT y de 9,8 años en TOS. Los pacientes con TPNM tuvieron significativamente mejor supervivencia que aquellos con SLPT o TOS. La incidencia de los tumores de novo (excluidos TPNM) fue 1.889/100.000 trasplantados/año. Por género, el cáncer de pulmón fue el TOS más común en varones y el cáncer de mama en mujeres. CONCLUSIÓN: En nuestro medio, excluidos los TPNM, la incidencia es 8,8 veces la estimada para la población general, con una alta tasa de cáncer de pulmón por lo que deberíamos implementar estrategias preventivas y diagnósticas

INTRODUCTION: The greater survival of transplanted patients is accompanied by an increase in the rate of de novo malignancies (NM), which are the most frequent late-onset complication. We can distinguish between non-melanoma skin cancers (NMSC), post-transplant lymphoproliferative disorders (PTLD) and solid organ cancers (SOC). Our objective is to determine the incidence of the different types of NM, the time elapsed until diagnosis and survival rates in our setting. METHODS: We conducted a retrospective study of 1071 liver transplant patients from 1990 to 2015 at our center. We analyzed the demographic variables, incidence of NM and survival. RESULTS: 184 NM developed in 1071 transplant patients (17%), specifically 19% of the males and 13% of the females (P=.004). The most frequent NM were NMSC (29%), lung (18%), head and neck (16%), PTLD (10%) and gastrointestinal (8%). The median time of diagnosis was 7.9 years in NMSC, 3.9 years in PTLD and 9.8 years in SOC. Patients with NMSC had significantly better survival than those with PTLD or SOC. The incidence of de novo tumors (excluding NMSC) was 1889/100,000 transplants/year. By gender, lung cancer was the most common TOS in men and breast cancer in women. CONCLUSION: In our setting, excluding NMSC, the incidence is 8.8 times greater than estimations for the general population, with a high rate of lung cancer, so we should implement preventive and diagnostic strategies

Incidence and survival rate of de novo tumors in liver transplants. / Incidencia y supervivencia de los tumores de novo en el trasplante hepático.

INTRODUCTION: The greater survival of transplanted patients is accompanied by an increase in the rate of de novo malignancies (NM), which are the most frequent late-onset complication. We can distinguish between non-melanoma skin cancers (NMSC), post-transplant lymphoproliferative disorders (PTLD) and solid organ cancers (SOC). Our objective is to determine the incidence of the different types of NM, the time elapsed until diagnosis and survival rates in our setting. METHODS: We conducted a retrospective study of 1071 liver transplant patients from 1990 to 2015 at our center. We analyzed the demographic variables, incidence of NM and survival. RESULTS: 184 NM developed in 1071 transplant patients (17%), specifically 19% of the males and 13% of the females (P=.004). The most frequent NM were NMSC (29%), lung (18%), head and neck (16%), PTLD (10%) and gastrointestinal (8%). The median time of diagnosis was 7.9 years in NMSC, 3.9 years in PTLD and 9.8 years in SOC. Patients with NMSC had significantly better survival than those with PTLD or SOC. The incidence of de novo tumors (excluding NMSC) was 1889/100,000 transplants/year. By gender, lung cancer was the most common TOS in men and breast cancer in women. CONCLUSION: In our setting, excluding NMSC, the incidence is 8.8 times greater than estimations for the general population, with a high rate of lung cancer, so we should implement preventive and diagnostic strategies.

1000 trasplantes hepáticos consecutivos. Análisis descriptivo y evolución de un centro / 1000 consecutive liver transplants. Descriptive analysis and evolution of a single center

Desde 1991 a 2013 se realizaron en el Hospital Virgen del Rocío 1.000 trasplantes hepáticos. Se realizó un estudio retrospectivo, en el que se analizaron las características de los donantes y los receptores, las indicaciones, la técnica quirúrgica, las complicaciones y la supervivencia en 2 etapas diferentes (1991-2002 vs. 2003-2013), coincidiendo con la implantación del MELD como modelo de priorización. La indicación más frecuente fue la hepatopatía de origen hepatocelular en 48,8%. Hubo un incremento significativo en las indicaciones por hepatocarcinoma (8,6% y 24,1% p = 0,03), y de la tasa retrasplantes (5,9% Vs 9,6%, p = 0,04). Se apreció un cambio en la edad de donación, pasando de 27,7 años en 1990 a 62,9 años en 2012 (p = 0,001). El porcentaje de pacientes que no precisaron transfusión de hemoderivados se duplicó (6,16 vs. 14,31%, p = 0,001). La supervivencia de todos los pacientes a uno, 5 y 10 años fue del 77, 63,5 y 51,3%, respectivamente

Between 1991 and 2013, 1,000 liver transplantations were performed at Virgen del Rocio Hospital (Seville, Spain). A retrospective study was conducted, analyzing the characteristics of recipients and donors, indications, surgical technique, complications and survival in 2 different stages (1991-2002 vs. 2003-2013) coinciding with the implementation of the MELD scale as a prioritization model. The most frequent indication were of hepatopathy of hepatocellular origin in 48.8%. There was a significant increase in the indications for hepatocarcinoma (8.6% and 24.1% P = 0.03), and the rate of retransplantation (5.9% vs 9.6%, P = 0.04). There was a change in the age of donation, going from 27.7 years in 1990 to 62.9 years in 2012 (P = 0.001). The percentage of patients who did not require blood transfusion doubled (6.16 vs. 14.31%, P = .001). Survival of all patients after one, 5 and 10 years was 77, 63.5 and 51.3%, respectively

1000 consecutive liver transplants. Descriptive analysis and evolution of a single center. / 1000 trasplantes hepáticos consecutivos. Análisis descriptivo y evolución de un centro.

Between 1991 and 2013, 1,000 liver transplantations were performed at Virgen del Rocio Hospital (Seville, Spain). A retrospective study was conducted, analyzing the characteristics of recipients and donors, indications, surgical technique, complications and survival in 2 different stages (1991-2002 vs. 2003-2013) coinciding with the implementation of the MELD scale as a prioritization model. The most frequent indication were of hepatopathy of hepatocellular origin in 48.8%. There was a significant increase in the indications for hepatocarcinoma (8.6% and 24.1% P=0.03), and the rate of retransplantation (5.9% vs 9.6%, P=0.04). There was a change in the age of donation, going from 27.7 years in 1990 to 62.9 years in 2012 (P=0.001). The percentage of patients who did not require blood transfusion doubled (6.16 vs. 14.31%, P=.001). Survival of all patients after one, 5 and 10 years was 77, 63.5 and 51.3%, respectively.

Is the sinusoidal obstructive syndrome post-liver transplantation a pathologic entity with a multifactorial etiology?

The sinusoidal obstructive syndrome is a complication typically associated with hematopoietic stem cell transplantation. This syndrome, more commonly known as veno-occlusive disease, has also been described after liver transplantation. It can have a life-threatening course. Herein, we describe the hepatic graft loss secondary to the development of a sinusoidal obstructive syndrome after a severe acute cellular rejection and toxic levels of once daily modified released tacrolimus (TAC). We discuss the role of the endotheliitis of acute rejection and toxic metabolites of some immunosuppressants such as azathioprine and TAC. Based on the current scientific evidence, we contemplate the possibility that the etiology of sinusoidal obstruction syndrome post-liver transplantation is multifactorial.

¿Es el síndrome de obstrucción sinusoidal asociado al trasplante hepático una entidad patológica con una etiología multifactorial? / Is the sinusoidal obstructive syndrome post-liver transplantation a pathologic entity with a multifactorial etiology?

El síndrome obstructivo sinusoidal hepático, anteriormente conocido como enfermedad veno-oclusiva, es una complicación típicamente asociada al trasplante de precursores hematopoyéticos. También se ha descrito su asociación con el trasplante hepático. Puede llegar a ser una causa de mortalidad. En este documento se describe la pérdida de un injerto hepático como consecuencia del desarrollo de un síndrome de obstrucción sinusoidal, insistiendo en la evolución del mismo y su relación con el rechazo agudo celular y los niveles tóxicos de tacrolimus en plasma. Basándonos en la evidencia actual, discutimos sobre la posibilidad de que la etiología del síndrome de obstrucción sinusoidal postrasplante hepático sea multifactorial, puesto que se relaciona con la endotelitis del rechazo agudo y los metabolitos tóxicos de algunos inmunosupresores, como la azatioprina y el tacrolimus (AU)

The sinusoidal obstructive syndrome is a complication typically associated with hematopoietic stem cell transplantation. This syndrome, more commonly known as veno-occlusive disease, has also been described after liver transplantation. It can have a life-threatening course. Herein, we describe the hepatic graft loss secondary to the development of a sinusoidal obstructive syndrome after a severe acute cellular rejection and toxic levels of once daily modified released tacrolimus (TAC). We discuss the role of the endotheliitis of acute rejection and toxic metabolites of some immunosuppressants such as azathioprine and TAC. Based on the current scientific evidence, we contemplate the possibility that the etiology of sinusoidal obstruction syndrome post-liver transplantation is multifactorial

Nitric Oxide Synthase Type III Overexpression By Gene Therapy Exerts Antitumoral Activity In Mouse Hepatocellular Carcinoma.

Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. Hepa 1-6 cells were used for in vitro and in vivo experiments. The first generation adenovirus was designed to overexpress NOS-3 (or GFP) and luciferase cDNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenoviruses were administered through the tail vein two weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-Luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8 activity in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by l-NAME or p53 siRNA. The tail vein infusion of AFP-NOS- 3/RSV-Luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

Prevention of cytomegalovirus disease using pre-emptive treatment after solid organ transplant in patients at high risk for cytomegalovirus infection.

BACKGROUND: The use of pre-emptive or prophylactic treatment to control cytomegalovirus (CMV) replication after solid organ transplant (SOT) remains controversial. The aim of this study was to evaluate whether administration of pre-emptive treatment to control viral replication guided by a highly sensitive diagnostic tool is an effective approach for preventing CMV disease, even in high-risk transplant recipients. METHODS: Plasma samples from eight SOT patients were tested using antigenaemia and real-time PCR (RT-PCR) assays. Pre-emptive treatment was administered guided by RT-PCR when viral load values were >1,000 copies/ml. RESULTS: All patients developed episodes of CMV infection, but none of them developed CMV disease or indirect effects. No patient in this study died or experienced graft rejection. Treatment was needed in 10 replication episodes. At the end of treatment, four had undetectable levels and the other six were cleared 3 weeks later. In 42.6% of tested samples RT-PCR was more sensitive for detecting viral infection. CONCLUSIONS: Pre-emptive monitoring of SOT patients at high risk for CMV infection protected patients from developing CMV disease during the first 6 months after transplant. The use of this sensitive method for guiding pre-emptive treatment diminished viral load early enough that it did not have consequences for patient health.