Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels.

Introduction: Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods: NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results: Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion: Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Lymphangioleiomyomatosis: Searching for potential biomarkers.

Background: Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers. Methods: We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination. Results: A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465-832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314-546) and 427 (365-513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (-6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%). Conclusion: Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs / Ensayo piloto de conservación pulmonar hipotérmica prolongada para analizar la lesión de isquemia-reperfusión en cerdos

Background: In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model. Methods: Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n=8) were submitted to organ procurement. Lungs were subjected to 6h (n=4) or 12h (n=4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30min after reperfusion, and (iv) 4h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker. Results: We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6h-CIT or 12h-CIT. IL-1β and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30min after reperfusion. (AU)

Antecedentes: En el trasplante de pulmón (TP), la duración del tiempo de isquemia es controvertida, ya que se estableció de forma arbitraria. Sería útil explorar el impacto del tiempo de isquemia fría (TIF) prolongado sobre la lesión de isquemia-reperfusión en un modelo experimental. Métodos: Ensayo piloto experimental aleatorizado de grupos paralelos y análisis ciego final utilizando un modelo de TP en cerdos. Se extrajeron los órganos de los animales donantes (n=8). Los pulmones se conservaron durante 6 horas (n=4) o 12 horas (n=4) en hipotermia aeróbica. El pulmón izquierdo se trasplantó y reperfundió durante 4 horas. Se obtuvieron biopsias de pulmón (i) al comienzo del TIF, (ii) al final del TIF, (iii) 30 minutos después de la reperfusión y (iv) 4 horas después de la reperfusión. Los injertos de pulmón se evaluaron histológicamente mediante la puntuación de daño histológico pulmonar y la relación de peso húmedo y peso seco. La respuesta inflamatoria se valoró mediante la determinación de citoquinas inflamatorias. Se determinó la actividad de caspasa-3 como marcador de apoptosis. Resultados: No observamos diferencias en la puntuación de daño histológico pulmonar o en la relación de peso húmedo y peso seco en un momento dado entre los pulmones sometidos a 6 h-TIF o 12 h-TIF. Las IL-1β e IL-6 mostraron una tendencia ascendente durante la reperfusión en ambos grupos. El TNF-α alcanzó su punto máximo dentro de los 30 minutos posteriores a la reperfusión. Apenas se detectó IFN-γ. La inmunoexpresión de caspasa-3 se clasificó semicuantitativamente por el porcentaje de células teñidas. Se observó un 20% de células apoptóticas 30 minutos después de la reperfusión. (AU)

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs.

BACKGROUND: In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model. METHODS: Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n=8) were submitted to organ procurement. Lungs were subjected to 6h (n=4) or 12h (n=4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30min after reperfusion, and (iv) 4h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker. RESULTS: We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6h-CIT or 12h-CIT. IL-1ß and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30min after reperfusion. CONCLUSIONS: We observed that 6 and 12h of CIT were equivalent in terms of microscopic lung injury, inflammatory profile and apoptosis in a LT swine model. The extent of lung injury measured by microscopic lung injury score, proinflammatory cytokines and caspase-3 determination was mild.

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs.

BACKGROUND: In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model. METHODS: Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n=8) were submitted to organ procurement. Lungs were subjected to 6h (n=4) or 12h (n=4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30min after reperfusion, and (iv) 4h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker. RESULTS: We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6h-CIT or 12h-CIT. IL-1ß and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30min after reperfusion. CONCLUSIONS: We observed that 6 and 12h of CIT were equivalent in terms of microscopic lung injury, inflammatory profile and apoptosis in a LT swine model. The extent of lung injury measured by microscopic lung injury score, proinflammatory cytokines and caspase-3 determination was mild.

Increasing kidney grafts for transplantation.

INTRODUCTION: The current pool of organs available for transplantation does not cover requirements, for this reason non-standard risk donors need to be incorporated into the pool. In this way, donors with small renal tumour are considered for transplantation after bench tumour excision. The aim of our study was to analyse our experience in using these grafts for transplantation. MATERIALS AND METHODS: Retrospective analysis from our prospective accrued database of donors with incidental renal mass used for kidney transplantation between January 2007 and August 2018. RESULTS: Twenty kidney transplantations were performed, thirteen cases received the affected kidney (after tumour removal) and seven the contralateral kidney; from six living and eleven deceased donors. Donor and recipient median age was 58 years (range 22-82) and 56.5 years (range 38-74), respectively. Mean tumour diameter was 12.7 mm (SD 9.5). Tumours resulted in two benign lesions and fifteen renal cell carcinoma. Surgical margins were negative. Two cases presented with bleeding after reperfusion was solved without repercussion. One case presented with immediate vein thrombosis. None of them present delayed graft function. After a 69 month follow-up none of the donors or the recipients presented tumour recurrence. CONCLUSIONS: Kidneys with small incidental tumours seem to be a good option for kidney transplantation in selected patients after bench surgery excision with good functional and oncologic results. More studies and longer follow-up are needed to confirm these results.

Obstructive sleep apnea and Fuhrman grade in patients with clear cell renal cell carcinoma treated surgically.

PURPOSE: To assess the association between obstructive sleep apnea (OSA) and Fuhrman grade in patients with clear cell renal cell carcinoma (ccRCC). As secondary endpoints, we studied its association with tumor size, metastasis-free survival (MFS) and cancer-specific survival (CSS). METHODS: We reviewed the databases of two tertiary care centers, identifying 2579 patients who underwent partial or radical nephrectomy for ccRCC between 1991 and 2014. Descriptive statistics were used to compare pathologic variables between patients with and without OSA. Linear and logistic regression models were used to assess the association of OSA with Fuhrman grade and tumor size. A Cox proportional hazards model was used to determine OSA association with MFS and CSS. A pathway analysis was performed on a cohort with available gene expression data. RESULTS: In total, 172 patients (7 %) had self-reported OSA at diagnosis. More patients with OSA had high Fuhrman grade compared to those without OSA [51 vs. 38 %; 13 % risk difference; 95 % confidence interval (CI), 5-20 %; p = 0.003]. On multivariable analysis, the association remained significant (OR 1.41; 95 % CI 1.00-1.99; p = 0.048). OSA was not associated with tumor size (p > 0.5), MFS (p = 0.5) or CSS (p = 0.4). A trend toward vascular endothelial growth factor pathway enrichment was seen in OSA patients (p = 0.08). CONCLUSIONS: OSA is associated with high Fuhrman grade in patients undergoing surgery for ccRCC. Pending validation of this novel finding in further prospective studies, it could help shape future research to better understand etiological mechanisms associated.

The Role of Surgery in Local Recurrences after Radical Cystectomy for Bladder Cancer.

INTRODUCTION: Local recurrence (LR) after radical cystectomy (RC) for bladder cancer has a bad prognosis. Treatment options include chemotherapy, radiation therapy and surgical excision, but few data is available on the advantages of surgery for these patients. PATIENTS AND METHODS: We evaluated our series of 8 selected patients who underwent surgery for locally recurrent bladder cancer after RC. RESULTS: The median time to recurrence after cystectomy was 20.8 months. The complications rate and severity were not negligible. Pathology report confirmed urothelial carcinoma with negative margins in all patients. After LR treatment, 4 patients recurred locally for a second time and 3 developed distant metastasis. They all died after a median follow-up of 10.4 months. One patient remained disease free after 14 months. CONCLUSIONS: The prognosis of patients with LR is poor regardless of surgical treatment and reflects the aggressive biological nature of urothelial tumors.

Kidneys from donors with incidental renal tumors: should they be considered acceptable option for transplantation?

BACKGROUND: The increase in the prevalence of end-stage renal disease in developed countries and the shortage of deceased donors has made it necessary to increase the graft pool by means of several strategies, such as live donation, non-heart-beating donors, and expanded criteria donors. Frequently, and because of the increasing acceptance of older donors, we find a higher percentage of incidental renal masses in these donors as a result of the inherent epidemiology of this disease. These kidneys can be considered suitable grafts after bench surgery to remove the tumor. METHODS: Retrospective analysis of donors with a diagnosis of incidental small renal mass before implantation and their corresponding recipients was performed between January 2007 and September 2012. All cases underwent an ex vivo tumorectomy with a preoperatory pathologic analysis. Recipients were followed up according to our standard renal tumor protocol. RESULTS: Eight donors with incidental renal mass were detected (four live and four deceased donors). The mean age was 47.8 years. Eleven transplantations were performed. Eight cases received the kidney after tumor exeresis, and three, the contralateral one. The recipient mean age was 53.8 years.The mean tumor diameter was 14.8 mm, with pathologic stages pT1a in seven cases and pT1b in one case (five clear cell renal carcinoma, two chromophobe type, and one lipoma). Surgical margins were negative. Mean follow-up was 32.34 months; none of the patients presented tumor recurrence, and all had correct renal function. CONCLUSIONS: Kidneys with small incidental tumors can be considered an option for kidney transplantation in selected patients.

El riesgo de reincidencia en agresores sexuales: in vestigación básica y valoración mediante el SVR_20 / Eviolence and sexual offender recidivism: basic research and risk assessment with SVR-2

El estudio de la violencia y de la reincidencia de los agresores sexuales constituye en la actualidad un ámbito de especial interés dela Psicología Criminal. En este trabajo se revisan tanto las teorías y conocimientos existentes sobre etiología y factores de riesgo deagresión sexual, como algunas investigaciones internacionales y españolas que sustentan estos conocimientos. Su principal objetivoes la presentación de un nuevo instrumento de predicción en este campo denominado SVR-20: Manual de valoración del riesgo deviolencia sexual. Dicho instrumento ha sido traducido y adaptado para el contexto español y latino por el Grupo de Estudios Avanzadosen Violencia (GEAV) de la Universidad de Barcelona. Para su validación se ha efectuado un primer estudio piloto sobre la capacidadpredictiva del SVR-20 con una muestra de agresores sexuales que cumplieron condena en una prisión española. La conclusión principal de este estudio es que el SVR-20 es un buen instrumento para predecir el riesgo de reincidencia sexual

Violence and sexual offenders’ recidivism are nowadays two fields of interest for Criminal Psychology. In this article, there is a reviewof theories and knowledge about the etiology and risk factors of sex aggression, and also of international and Spanish research thatsupports this theoretical foundation. The main goal of this study is to introduce an instrument for risk assessment called SVR-20:Guide for sexual violence risk assessment. This instrument has been translated and adapted for the Spanish context by the Group inAdvanced Studies on Violence (GEAV) of the University of Barcelona. In order to validate this instrument, a pilot study about the predictiveaccuracy of the SVR-20 has been carried out, using a sample of incarcerated sex offenders from a Spanish prison. The mainconclusion of this study is that SVR-20 is a good instrument to predict the risk of sexual recidivism (AU)