RESUMEN
The lower gastrointestinal tract (LGI) and liver are the GVHD target organs most associated with treatment failure and nonrelapse mortality. We recently identified regenerating islet-derived 3-α (REG3α) as a plasma biomarker of LGI GVHD. We compared REG3α with 2 previously reported GI and liver GVHD diagnostic biomarkers, hepatocyte growth factor (HGF) and cytokeratin fragment 18, in 954 hematopoietic cell transplantation patients. All 3 biomarkers were significantly elevated in LGI GVHD compared with non-GVHD diarrhea; REG3α discerned LGI GVHD from non-GVHD diarrhea better than HGF and cytokeratin fragment 18. Although all 3 biomarkers predicted nonresponse to therapy at day 28 in LGI GVHD patients, only REG3α and HGF concentrations predicted 1-year nonrelapse mortality (P = .01 and P = .02, respectively). Liver GVHD without GI involvement at GVHD onset and non-GVHD liver complications were uncommon; all 3 biomarkers were elevated in liver GVHD, but did not distinguish GVHD from other causes of hyperbilirubinemia.
Asunto(s)
Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Enfermedad Injerto contra Huésped/sangre , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Lectinas Tipo C/sangre , Adolescente , Adulto , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Tracto Gastrointestinal/patología , Enfermedad Injerto contra Huésped/mortalidad , Factor de Crecimiento de Hepatocito/sangre , Humanos , Lactante , Recién Nacido , Queratina-18/sangre , Hígado/patología , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Pancreatitis , Curva ROC , Adulto JovenRESUMEN
Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 51 patients by liquid chromatography-tandem mass spectrometry. Samples were collected between admission and day 90 after transplantation, and metabolite levels were correlated with early clinical events and outcome. In selected patients, IDO gene expression was assessed by quantitative RT-PCR in intestinal biopsies. Surviving patients had significantly lower metabolite levels on days 28, 42, and 90, respectively, compared with patients dying of GVHD and associated complications (n = 10). Kynurenine levels were directly correlated with severity and clinical course of GVHD: Mean urinary quinolinic acid levels were 4.5 ± 0.3 µmol/mmol creatinine in the absence of acute GVHD, 8.0 ± 1.1 µmol/mmol creatinine for GVHD grade 1 or 2, and 13.5 ± 2.7 µmol/mmol creatinine for GVHD grade 3 or 4 (P < .001), respectively. GVHD-dependent induction of IDO was further suggested by increased expression of IDO mRNA in intestinal biopsies from patients with severe GVHD. Our data indicate reactive release of kynurenines in GVHD-associated inflammation.
Asunto(s)
Enfermedad Injerto contra Huésped/orina , Trasplante de Células Madre Hematopoyéticas/métodos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Triptófano/orina , Adolescente , Adulto , Anciano , Cromatografía Liquida , Regulación Enzimológica de la Expresión Génica , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patología , Quinurenina/metabolismo , Quinurenina/orina , Espectrometría de Masas , Persona de Mediana Edad , Ácido Quinolínico/metabolismo , Ácido Quinolínico/orina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Factores de Tiempo , Trasplante Homólogo , Triptófano/metabolismo , Adulto JovenRESUMEN
There are no plasma biomarkers specific for GVHD of the gastrointestinal (GI) tract, the GVHD target organ most associated with nonrelapse mortality (NRM) following hematopoietic cell transplantation (HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GVHD, 74 proteins were increased at least 2-fold; 5 were of GI origin. We validated the lead candidate, REG3α, by ELISA in samples from 1014 HCT patients from 3 transplantation centers. Plasma REG3α concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients and correlated most closely with lower GI GVHD. REG3α concentrations at GVHD onset predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P ≤ .001). In a multivariate analysis, advanced clinical stage, severe histologic damage, and high REG3α concentrations at GVHD diagnosis independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present: 25% for patients with 0 risk factors to 86% with 3 risk factors present (P < .001). REG3α is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients.
Asunto(s)
Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Biomarcadores/sangre , Enfermedad Injerto contra Huésped/sangre , Lectinas Tipo C/sangre , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Niño , Preescolar , Tracto Gastrointestinal/patología , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Datos de Secuencia Molecular , Análisis Multivariante , Proteínas Asociadas a Pancreatitis , Valor Predictivo de las Pruebas , Pronóstico , Proteómica/métodos , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
The progression of acute pancreatitis to necrotizing pancreatitis which often results in high morbidity and mortality is difficult to predict. Here we report that serum concentrations of sCD137 are increased in patients with acute pancreatitis. Admission levels and 10-day median sCD137 levels positively correlate with markers of biliary pancreatitis and the 10-day sCD137 median is significantly higher in metabolic than in alcoholic pancreatitis. Serum concentrations of sCD137 at time of admission and the 10-day median of sCD137 correlate with the Ranson and APACHE II disease scores but not with the radiological Balthazar and Schroeder scores that reflect pancreatic and peripancreatic necrosis. Further, sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis.
Asunto(s)
Pancreatitis/patología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangre , APACHE , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Páncreas/patología , Pancreatitis/clasificación , Pancreatitis/complicaciones , Pancreatitis/mortalidad , Pronóstico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
OBJECTIVES: Adipocytes of peripancreatic and intrapancreatic adipose tissue secret adipocytokines such as leptin, adiponectin, and resistin. For resistin, a role as an early predictor of peripancreatic necrosis and clinical severity in acute pancreatitis has been reported. It was the aim of this study to investigate whether the adipocytokine visfatin is able to serve as an early marker predicting peripancreatic necrosis and clinical severity. METHODS: A total of 50 patients (20 females and 30 males) with acute pancreatitis were included in this noninterventional, prospective, and monocentric cohort study on diagnostic accuracy. Clinical severity was classified by the Ranson score and APACHE-II (Acute Physiology and Chronic Health Evaluation II) score. Pancreatic and peripancreatic necrosis were quantified by the computed tomography-based Balthazar score, the Schroeder score, and the pancreatic necrosis score. Visfatin was measured at admission and daily for 10 days by enzyme-linked immunosorbent assay (ELISA). RESULTS: Visfatin values were significantly and positively correlated with clinical severity (APACHE-II score and Ranson score) and with clinical end points such as death and need for interventions. Admission visfatin levels were significantly elevated in patients with higher pancreatic and extrapancreatic necrosis scores. It was shown by receiver operator characteristics that admission visfatin concentration provides a positive predictive value of 93.3% in predicting the extent of peripancreatic necrosis (area under the curve (AUC): 0.89, P<0.001, sensitivity: 93.3%, specificity: 81.8%, likelihood ratio: 5.1, post-test probability: 93%) by using a cutoff value of 1.8 ng/ml. CONCLUSIONS: Admission visfatin concentration serves as an early predictive marker of peripancreatic necrosis and clinical severity in acute pancreatitis. Visfatin may have potential for clinical use as a new and diagnostic serum marker.
Asunto(s)
Adipoquinas/sangre , Nicotinamida Fosforribosiltransferasa/sangre , Pancreatitis Aguda Necrotizante/diagnóstico , Pancreatitis/diagnóstico , APACHE , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Pancreatitis/diagnóstico por imagen , Pancreatitis/patología , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/patología , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
OBJECTIVES: Peripancreatic necrosis determines clinical severity in acute pancreatitis. Early markers predicting peripancreatic necrosis and clinical severity are lacking. Because adipocytes of peripancreatic adipose tissue secret highly active adipocytokines, the aim of the study was to investigate whether adipocytokines are able to serve as early markers predicting peripancreatic necrosis and clinical severity. METHODS: A total of 50 patients (20 women, 30 men) with acute pancreatitis were included in this noninterventional, prospective, and monocentric cohort study on diagnostic accuracy. Clinical severity was classified by the Ranson score and the APACHE (Acute Physiology And Chronic Health Evaluation) II score. Pancreatic and peripancreatic necrosis were quantified by using the computed tomography-based Balthazar score, the Schroeder score, and the pancreatic necrosis score. Adiponectin, leptin, and resistin were measured at admission and daily for at least 10 days by enzyme-linked immunosorbent assay. RESULTS: In contrast to admission C-reactive protein values, admission resistin values were significantly correlated with clinical severity and even with clinical end points such as death and need for interventions. Admission resistin levels were significantly elevated in patients with higher pancreatic and extrapancreatic necrosis scores. It was shown by receiver-operator characteristics that admission resistin concentration provides a positive predictive value of 89% in predicting the extent of peripancreatic necrosis (area under the curve, 0.8; P=0.002; sensitivity, 80%; specificity, 70%) by using a cutoff value of 11.9 ng/ml. CONCLUSIONS: Admission resistin concentration serves as an early predictive marker of peripancreatic necrosis and clinical severity in acute pancreatitis. Resistin may have potential for clinical use as a new and diagnostic serum marker.
Asunto(s)
Páncreas/patología , Pancreatitis Aguda Necrotizante/sangre , Resistina/sangre , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Páncreas/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/patología , Selección de Paciente , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Curva ROC , Radiografía , Sensibilidad y EspecificidadRESUMEN
Both indirect and direct effects contribute to changes in the clinical presentation of graft-versus-host disease (GvHD) after reduced-intensity conditioning (RIC) compared with standard intensity regimens. A delay in acute GvHD after RIC may be explained by reduced conditioning-related inflammation and by altered allostimulatory capacities of recipient antigen-presenting cells (APC). A higher frequency of chronic GvHD results from the almost exclusive use of peripheral blood stem cells, the absence of tolerance induction by current regimens for prophylactic immunosuppression and modified kinetics in the replacement of recipient APC. Established acute and chronic GvHD requires standard treatment irrespective of the type of conditioning. To improve long-term outcome in GvHD, pre-emptive strategies or more selective approaches aimed at immunomodulation rather than immunosuppression are needed.
Asunto(s)
Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/fisiopatología , Trasplante de Células Madre/efectos adversos , Acondicionamiento Pretrasplante/métodos , Alemtuzumab , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/uso terapéutico , Células Presentadoras de Antígenos/inmunología , Antineoplásicos/uso terapéutico , Etanercept , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunoglobulina G/uso terapéutico , Inflamación , Prednisolona/administración & dosificación , Receptores del Factor de Necrosis Tumoral/uso terapéuticoRESUMEN
BACKGROUND AND AIM: Severe acute pancreatitis is characterized by lipase-induced peripancreatic fat cell necrosis. Because adipocytes secret several highly active molecules, the aim of the present study was to investigate the hypothesis that adipocytokines could serve as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis. METHODS: A total of 23 patients (11 females, 12 males) with acute pancreatitis were included and a computed tomography (CT) examination was available in 20 patients. Balthazar score, Schröder score, pancreatic necrosis score, Ranson score and APACHE II score were calculated, correlated with biochemical parameters and analyzed using receiver-operator characteristics (ROC) analysis. Adipocytokine serum levels were measured daily by enzyme-linked immunosorbent assay (ELISA) over 10 days after admission. RESULTS: Resistin and leptin were significantly elevated in patients with severe pancreatitis and were correlated with a radiological scoring system for extrapancreatic necrosis. Whereas resistin correlated positively with clinical scoring systems, time until discharge and the need for interventions, leptin was correlated positively with C-reactive protein (CRP) levels. Resistin levels measured on the day of admittance had a positive predictive value of 93.3% (cut-off: >6.95 ng/mL) in predicting a Schröder score >3. CONCLUSION: Resistin, and to a lesser extent leptin, but not adiponectin levels are novel potential markers for extrapancreatic necrosis and severity of acute pancreatitis and should therefore be tested in larger cohorts of patients.