Higher Expression of Activated CD8+ T Lymphocytes (CD8+CD25+, CD8+CD69+ and CD8+CD95+) Mediate Early Post-Transplant Acute Tubular Injury in Kidney Recipients.

BACKGROUND: Acute kidney injury (AKI) is a leading cause of early post-transplant kidney damage. Furthermore, acute tubular necrosis (ATN) is appointed as the most prevalent form of AKI, a frequent multifactorial process associated with high morbidity and mortality, yet giving rise to delayed graft function (DGF) and, ultimately, allograft dysfunction. Common factors such as prolonged cold ischemia time, advanced donor age, cadaveric versus living donor, donor history of hypertension, as well as donation after cardiac death have all been deemed risk factors for ATN. With the increasing number of older cadaveric and cardiac donors in the donation process, ATN could have a detrimental impact on patient welfare. Therefore understanding the underlying process would benefit the transplant outcome. We aimed to prospectively monitor several T cell subsets in a cohort of kidney transplant recipients (KTrs) to investigate whether there is an adaptive immune-mediated involvement in the ATN process. METHODS: Peripheral blood was collected from 31 KTrs at different time points within the first-year post-transplantation for in vitro stimulation with Concanavalin-A (Con-A) in a humidified 5% CO2 incubator at 37 °C for 72 hours. Upon cell stimulation, flow cytometry was applied to quantify the surface expression through the median fluorescence intensity (MFI) of CD4+CD25+, CD8+CD25+, CD4+CD38+, CD8+CD38+, CD4+CD154+, CD8+CD154+, CD4+CD69+, CD8+CD69+, CD4+CD95+, and CD8+CD95+ T cells. Statistical analysis was carried out with SPSS Statistics IBM v.25 (IBM Corp, Armonk, NY, USA). MFIs values were compared using a univariate analysis by a nonparametric U-Mann Whitney test. ROC analysis was applied to define cut-off values most capable of stratifying patients at high risk of ATN. Spearman's rank-order coefficient test was applied to correlate biomarkers with allograft function. Multivariate regression independently validated CD8+ T lymphocytes as surrogate biomarkers of ATN. A p-value < 0.05 was considered statistically significant. RESULTS: KTrs who developed ATN upon transplantation had significantly higher expression of CD25, CD69, and CD95 on CD8+ and lower expression of CD95 on CD4+ T lymphocytes than patients with stable graft function. ROC curve analysis showed that MFIs ≥1015.20 for CD8+CD25+, ≥2489.05 for CD8+CD69+, ≥4257.28 for CD8+CD95+, and ≤1581.98 for CD4+CD95+ were capable of stratifying KTrs at high risk of ATN. Furthermore, patients with an MFI below any cut-off were significantly less likely to develop ATN than those with other values. The allograft function was correlated with the CD4+CD95+/CD8+CD95+ ratio in KTrs who developed ATN. The multivariate analysis confirmed that, within the first-month post-transplant, MFI values of CD8+CD25+, CD4+CD95+, and CD8+CD95+ T lymphocytes, along with donor age, serum creatinine, and GFR were independent risk factors to ATN. Moreover, we were also able to corroborate previous immune factors of importance in immune-mediated response to the allograft, such as the patient's maximum panel reactive antibody (PRA) or the maintenance immunosuppression therapy. CONCLUSIONS: Our results demonstrate evidence for the implication of CD8+ T lymphocytes in the development of ATN early in the post-transplant phase. Post-transplant monitoring of activated CD8+ T lymphocytes may help identify which patients require further clinical intervention to prevent graft damage.

Biomarkers of Early Liver Graft Damage in Circulatory Death and Brain Death Donors: A Propensity Score Matching Analysis.

BACKGROUND: Donation after circulatory death (DCD) is related to a warm ischemia time and more complications compared with traditional donors (donation after brain death [DBD]). METHODS: This study included biopsy samples retrospectively collected from November 2014 to December 2018 to compare histologic and biological markers of DCD and DBD liver grafts. The analysis includes marker of early apoptosis (p21), senescence (telomerase reverse transcriptase [TERT]), cell damage (caspase-3 active), endothelial damage (vascular endothelial growth factor), stem cell (CD90), hypoxia (HIF1A), inflammatory activation (COX-2), and cross-organ allograft rejection (CD44). A propensity score matching (PSM) was used to match patients receiving DCD livers to those receiving DBD livers. We analyzed the immunohistochemical initial liver damage-related warm ischemia time. RESULTS: Positive staining expression of liver damage biomarkers (COX-2, CD44, TERT, HIF1A, and CD90) was found, but no significant differences were found between DCD and DBD and with ischemic cholangiopathy. After PSM, there was a significant relationship between CD90 and male donors (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.07-0.91), TERT with donor sodium (OR, 1.11; 95% CI, 1.02-1.2), HIF1A with steatosis (OR, 0.33; 95% CI, 0.13-0.83), and CD44 with donor vasoactive drugs (OR, 0.36; 95% CI, 0.13-1) and glutamic oxaloacetic transaminase 1 week increase (OR, 1.01; 95% CI, 1-1.03). CONCLUSIONS: DCD immunohistochemical initial liver damage was found to behave similarly to DBD. The increase in complications and cholangiopathy associated with warm ischemia could be related to a different later phenomenon.

Personalized Medicine for Kidney Transplantation: Association of Graft Survival and Acute Transplant Rejection with Genetic Variation in B Cell Activating Factor System Signaling.

Kidney transplantation (KT) clinical outcomes are highly variable across patients and would benefit from predictive biomarkers to achieve personalized/precision medicine. The B cell activating factor (BAFF) system signaling plays an essential role in B lymphocytes' homeostasis, and is implicated in activation and survival of B lymphocytes. Single nucleotide polymorphisms (SNPs) in BAFF system genes are therefore strong candidates to identify the genetic mechanisms underpinning variable clinical outcomes in KT. We report here new findings on BAFF system genetic polymorphisms in KT patients in relation to two key phenotypes of clinical interest: graft survival and acute rejection (AR). A total of 168 KT patients, of which 29 suffered AR, participated in this study. The BAFF system polymorphisms in five genes TNFSF13B, TNFSF13, TNFRSF13C, TNFRSF13B, and TNFRSF17 were characterized using TaqMan SNP genotyping. Patients with KT who had an AA genotype in polymorphism rs3803800 of the TNFSF13 gene had a higher risk of suffering AR (p = 0.046; odds ratios = 3.38, 95% CI: 1.02-11.2). Moreover, patients with AA genotype (rs3803800) in the TNFSF13 gene had a significantly lower AR-free time than the GG/GA genotypes (69.2% vs. 85.7%; p = 0.037). Of importance, bioinformatics analysis showed that the polymorphism rs3803800 could alter splicing regulation and affect the proliferation-inducing ligand (APRIL) expression levels. The analysis of graft survival did not show a significant association with the polymorphisms analyzed in this study. In conclusion, the rs3803800 genetic polymorphism from this study of BAFF system genes appears to display importance in AR-free time for KT patients, and thus, warrants further research in independent populations as a putative predictive biomarker of AR. These findings also inform future personalized/precision medicine efforts and functional genomic studies in KT patients.

Utilidad de la 18-fluorodeoxiglucosa en la tomografía por emisión de positrones-tomografía computarizada (PET-TC) preoperatoria en el diagnóstico precoz del cáncer de páncreas exocrino: estudio en 139 casos resecados / Utility of 18 fludeoxyglucose in preoperative positon-emission tomography-computed tomography (PET-CT) in the early diagnosis of exocrine pancreatic cancer: A study of 139 resected cases

INTRODUCCIÓN: El único tratamiento curativo del cáncer de páncreas (CP) es la exéresis quirúrgica, pero debido a su presentación clínica tardía solo el 15-25% de los pacientes son candidatos a resección curativa. El objetivo de este trabajo, prospectivo y unicéntrico, es determinar la utilidad de la PET-TC preoperatoria en el diagnóstico precoz del CP, en su estadificación y en la detección de estadios precursores de la enfermedad en una serie de 139 pacientes sometidos a intervención quirúrgica con «intención curativa» y con el diagnóstico histológico de adenocarcinoma ductal. MÉTODOS: Hemos estudiado las características histopatológicas del CP y de las diferentes lesiones panIN en las piezas quirúrgicas de 139 pacientes sometidos a resección pancreática durante el periodo 2010-2014, comparando estos resultados con los datos preoperatorios de una tomografía computarizada multidetector con contraste trifásico (TCMD) y una PET-TC en la que la captación de glucosa fue determinada por el SUV, considerando malignidad por encima de 2,5. RESULTADOS: En nuestra serie, la sensibilidad de la PET-TC para el diagnóstico tumoral fue del 77,7% (108 de los 139 casos) versus el 75,5% (105 de los 139 casos) para la TCMD. Cuando combinamos este valor máximo del SUV tumoral con el SUV máximo de tejido pancreático normal de cada paciente, la sensibilidad diagnóstica de la PET-TC para el CP asciende al 94,9% (132 de los 139 casos). CONCLUSIÓN: Una combinación de los estudios del PET-TC en el tejido tumoral y no tumoral de cada paciente puede ser una herramienta diagnóstica muy útil no solo para el diagnóstico preoperatorio del CP, sino también para las lesiones panIN

INTRODUCTION: In pancreatic ductal adenocarcinoma (PDA), surgical resection is the only curative treatment, but due to its late clinical presentation only 15-25% patients are candidates for curative resection. The aim of this prospective, single-center study is to determine the diagnostic utility of preoperative PET-CT for early detection of PDA and early panIN lesions. METHODS: We studied the histopathological features of PDA and different panIN lesions in 139 surgical samples from patients undergoing pancreatic resection (from 2010-2014), comparing these results with preoperative PET-CT and MDCT study. For tumor diagnosis in PET-CT maximum standard SUV 2.5 was used. Pancreatic baseline SUVmax is the maximum uptake of the radiotracer 18-2FDG on the ROI curve determined for the area of the normal pancreas after pathological reassessment with areas not affected by tumours or preneoplastic lesions. Tumour Uptake Index is the ratio between the tumour SUVmax and pancreatic baseline SUVmax. RESULTS: Using an standard maximum SUV value of 2.5, PET-CT sensitivity was 77.7% (108 of the 139 cases) against 75.5% (105 of the 139 cases) of MDCT. But when we combined this value with maximum SUV of normal pancreatic tissue from each patient, PET-CT sensitivity improved its value to 94.9%. CONCLUSION: A combination of studies of PET-CT in tumor and non-tumor tissue of each patient might be a very useful diagnostic tool not only for preoperative diagnosis of PDA, but also for early panIN lesions

Paquidermodactilia clásica. Una simuladora de artritis idiopática juvenil / Classic pachydermodactyly. A simulator of juvenile idiopathic arthritis

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Factores pronósticos de los tumores neuroendocrinos de páncreas resecados. Experiencia en 95 pacientes / Prognostic factors in resected pancreatic neuroendocrine tumours: Experience in 95 patients

INTRODUCCIÓN: El objetivo de este estudio fue analizar los factores pronósticos que influyen en la supervivencia y en la recidiva en una serie de pacientes diagnosticados de tumores neuroendocrinos de páncreas (TNEP) y tratados mediante resección quirúrgica. MÉTODOS: Serie retrospectiva de 95 pacientes intervenidos y resecados de TNEP. Las variables estudiadas son: edad, sexo, forma de presentación (esporádica/familiar), funcionalidad, tipo de tumor, localización, cirugía realizada, tamaño tumoral, multifocalidad, tasa de curación y de recidiva. Se ha utilizado la nueva clasificación de la OMS en 2010. RESULTADOS: De los 95 pacientes, 45 eran varones y 50 mujeres, con una edad media de 47,6 años. Presentación esporádica en 66 pacientes (69,8%) y familiar en los 29 restantes (30,2%), asociados a síndrome MEN 1. El 59% (56 pacientes) eran no funcionantes y el 41% restante funcionantes. Los TNEP funcionantes incluían 20 insulinomas, 16 gastrinomas y 3 glucagonomas. La técnica quirúrgica más utilizada (42 pacientes) fue la pancreatectomía corporocaudal. Según la clasificación de la OMS (2010), 59 pacientes presentaban un TNEP G1, 24 un TNEP G2 y los 12 pacientes restantes un carcinoma pobremente diferenciado. La supervivencia a los 5 años en los tumores bien diferenciados ha sido del 100%, independientemente de la funcionalidad. Los TNE esporádicos suelen ser unifocales (p < 0,001) y se asocian a metástasis hepáticas. El seguimiento medio ha sido de 85,3 meses, con una tasa de supervivencia del 65,8% y de recidiva del 24%. CONCLUSIONES: En nuestra experiencia, la clasificación de la OMS (2010) es un factor pronóstico independiente en la supervivencia de los TNEP

INTRODUCTION: The aim of this study was to analyze prognostic factors for survival and recurrence in patients with resected pancreatic neuroendocrine tumors (PNT). METHODS: Medical records of 95 patients with resected PNT were retrospectively reviewed. The variables studied were: age, sex, form of presentation (sporadic/familial tumors), functionality, type of tumor, localization, type of surgery, tumor size, multifocal tumors and recurrent rate. The new WHO classification (2010) was used. RESULTS: There were 45 men and 50 women. Mean age was 46.8 years. Regarding the mode of presentation, it was sporadic in 66 patients (69.8%) and 29 cases were familial neuroendocrine tumors (30.2%) in association with MEN 1 syndrome. The 59% of patients suffered from non-functional tumors and 41% were functional: 20 insulinoma, 16 gastrinoma, and 3 glucagonoma. Distal pancreatectomy was the most common surgical procedure, followed by tumor enucleation in 19 patients. According to the WHO classification, 59 patients had a PNT G1, 24 PNT G2 and 12 with a poorly-differentiated carcinoma, respectively. The 5-year survival in well-differentiated tumors was 100%, regardless of the functionality. Sporadic PNT are more commonly unifocal (P<0.001), associating liver metastasis. Survival and recurrence rates after a mean follow-up of 85.3 months were 65.8 and 24%, respectively. CONCLUSIONS: In our experience, WHO classification was an independent prognostic factor in PNT survival

Pancreatitis del surco versus adenocarcinoma de páncreas: a propósito de 8 casos / Groove pancreatitis vs. pancreatic adenocarcinoma: A review of 8 cases

INTRODUCCIÓN: La pancreatitis del surco (PS) es una entidad poco frecuente que clínica y radiológicamente puede simular un carcinoma del área periampular. El objetivo de este trabajo es presentar una serie de 8 pacientes que fueron intervenidos quirúrgicamente con el diagnóstico preoperatorio de masa en cabeza pancreática, con un diagnóstico anatomopatológico definitivo de PS. Metodos: En nuestra serie, 6 eran hombres y 2 mujeres y tenían una edad media de 51,9 años. Previamente a la cirugía, todos los pacientes presentaban dolor abdominal en epigastrio que requería analgesia a altas dosis. En la analítica preoperatoria, el CEA y el Ca 19.9 fueron normales en todos los pacientes. Los estudios de imagen mostraron lesiones sólidas intrapancreáticas en 6 de los 8 pacientes, y en los 2 restantes una masa mamelonada de 5 y 6 cm, respectivamente, que estenosaba la luz duodenal. La ecoendoscopia fue negativa para células neoplásicas en todos los pacientes. RESULTADOS: La evolución durante el postoperatorio inmediato fue satisfactoria, sin complicaciones. En nuestra serie, no ha fallecido ningún paciente. La evolución a largo plazo, en 7 de los 8 pacientes, ha sido excelente, con desaparición del dolor abdominal y mejoría del estado nutricional. El caso restante ha tenido frecuentes episodios de pancreatitis aguda recidivante y, a los 60 meses, ha presentado un seudoquiste que ha precisado una quistoyeyunostomía en Y de Roux. CONCLUSIONES: La PS debe incluirse en el diagnóstico diferencial de lesiones pancreáticas, que pueden incluir carcinoma del área periampular y otras causas de pancreatitis crónica

INTRODUCTION: Groove pancreatitis (PS) is an uncommon clinical situation and radiologically it can mimic carcinoma of the periampullary area. The aim of this paper is to study a series of 8 patients who underwent surgery with preoperative diagnosis of pancreatic head mass and subsequent pathological diagnosis of PS. METHODS: In our series, 6 were men and 2 women, with an average age of 51,9 years. Before surgery, all patients had epigastric abdominal pain requiring analgesia at high doses. The preoperative analytical CEA and Ca 19.9 were normal in all patients. Imaging studies showed intrapancreatic solid lesions in 6 of the 8 patients, and in the remaining 2 one papillary mass of 5 and 6 cm, respectively, that caused stenosis in the duodenal luz. EUS neoplastic cells were negative in all patients. RESULTS: The immediate postoperative evolution was satisfactory, there are no complications. In our series, no patients have died. The long-term follow-up, in 7 of the 8 patients, has been excellent with disappearance of abdominal pain and improvement of nutritional status. The remaining patient had frequent recurrent episodes of acute pancreatitis, and at 60 months, presented a pseudocyst that has required a Roux-en-Y cystojejunostomy. CONCLUSIONS: PS must be included in the differential diagnosis of pancreatic lesions, which may include carcinoma of the periampullary area and other causes of chronic pancreatitis

Una nueva técnica quirúrgica para la hepatectomía derecha extendida: torniquete en la cisura umbilical y oclusión portal derecha (ALTPS). Caso clínico / A new surgical technique for extended right hepatectomy: Tourniquet in the umbilical fissure and right portal vein occlusion (ALTPS). Clinical case

Associating liver partition and portal vein ligation for staged (ALPPS) para las resecciones hepáticas en 2 tiempos, consigue la hipertrofia del volumen funcional residual (VFR) en 7 días, al ocluir las colaterales intrahepáticas entre ambos lóbulos. En marzo de 2012 publicamos una nueva técnica quirúrgica, asociando la colocación de un torniquete en la línea de Cantlie con ligadura portal derecha (Associating liver tourniquet and right portal vein occlusion for staging hepatectomy [ALTPS]). Ahora presentamos la técnica ALTPS en la cisura umbilical para hipertrofiar los segmentos II - III , realizada en un varón de 51 años con recidiva de hipernefroma renal derecho que invade todo el lóbulo derecho y la vena cava inferior. El VFR preoperatorio fue de 380 ml (20% del total) y aumentó un 150% a los 7 días (a 953 ml; 31% del total). En el segundo tiempo se realizó trisectorectomía derecha con resección de la vena cava inferior retrohepática, siendo sustituida por un injerto de goretex anillado de 2 cm de diámetro (AU)

ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), in 2-stage liver resections, achieves hypertrophy of the functional liver remnant (FLR) in 7 days, and the objective of this technique is the occlusion of the intrahepatic collaterals. In March 2012 we published a new surgical technique associating the insertion of a tourniquet in Cantlie’ line and right portal vein ligation (ALTPS: Associating liver tourniquet and right portal vein occlusion for staged hepatectomy). In this paper we present this ALTPS technique placing the tourniquet in the umbilical fissure to obtain hypertrophy of segments II - III . It was performed in a 51 year-old patient with a recurrent right renal hypernephroma which involved all the anatomic right lobe and inferior vena cava. Preoperative FLR was 380 ml (20% of the total volume) increasing 150% at 7 days (to 953 ml, 31% of the total). In the second step, we performed a right trisectionectomy and retrohepatic inferior vena cava resection, replacing it by a 2 cm-ring goretex graft (AU)