PD-1/PD-L1 axis: implications in immune regulation, cancer progression, and translational applications.

The PD-1/PD-L1 axis is a complex signaling pathway that has an important role in the immune system cells. Programmed cell death protein 1 (PD-1) acts as an immune checkpoint on the T lymphocytes, B lymphocytes, natural killer (NK), macrophages, dendritic cells (DCs), monocytes, and myeloid cells. Its ligand, the programmed cell death 1 ligand (PD-L1), is expressed in the surface of the antigen-presenting cells (APCs). The binding of both promotes the downregulation of the T cell response to ensure the activation to prevent the onset of chronic immune inflammation. This axis in the tumor microenvironment (TME) performs a crucial role in the tumor progression and the escape of the tumor by neutralizing the immune system, the engagement of PD-L1 with PD-1 in the T cell causes dysfunctions, neutralization, and exhaustion, providing the tumor mass production. This review will provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management.

Prognostic Value of Histone Acetyl Transferase 1 (HAT-1) and Inflammatory Signatures in Pancreatic Cancer.

Pancreatic cancer is a type of gastrointestinal tumor with a growing incidence and mortality worldwide. Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of cases, and late-stage diagnosis is common, leading to a 5-year survival rate of less than 10% in high-income countries. The use of biomarkers has different proven translational applications, facilitating early diagnosis, accurate prognosis and identification of potential therapeutic targets. Several studies have shown a correlation between the tissue expression levels of various molecules, measured through immunohistochemistry (IHC), and survival rates in PDAC. Following the hallmarks of cancer, epigenetic and metabolic reprogramming, together with immune evasion and tumor-promoted inflammation, plays a critical role in cancer initiation and development. In this study, we aim to explore via IHC and Kaplan-Meier analyses the prognostic value of various epigenetic-related markers (histones 3 and 4 (H3/H4), histone acetyl transferase 1 (HAT-1), Anti-Silencing Function 1 protein (ASF1), Nuclear Autoantigenic Sperm Protein (NASP), Retinol Binding Protein 7 (RBBP7), importin 4 (IPO4) and IPO5), metabolic regulators (Phosphoglycerate mutase (PGAM)) and inflammatory mediators (allograft inflammatory factor 1 (AIF-1), interleukin 10 (IL-10), IL-12A and IL-18) in patients with PDAC. Also, through a correlation analysis, we have explored the possible interconnections in the expression levels of these molecules. Our results show that higher expression levels of these molecules are directly associated with poorer survival rates in PDAC patients, except in the case of IL-10, which shows an inverse association with mortality. HAT1 was the molecule more clearly associated with mortality, with a hazard risk of 21.74. The correlogram demonstrates an important correlation between almost all molecules studied (except in the case of IL-18), highlighting potential interactions between these molecules. Overall, our study demonstrates the relevance of including different markers from IHC techniques in order to identify unexplored molecules to develop more accurate prognosis methods and possible targeted therapies. Additionally, our correlation analysis reveals potential interactions among these markers, offering insights into PDAC's pathogenesis and paving the way for targeted therapies tailored to individual patient profiles. Future studies should be conducted to confirm the prognostic value of these components in PDAC in a broader sample size, as well as to evaluate the possible biological networks connecting them.

Autophagy in Its (Proper) Context: Molecular Basis, Biological Relevance, Pharmacological Modulation, and Lifestyle Medicine.

Autophagy plays a critical role in maintaining cellular homeostasis and responding to various stress conditions by the degradation of intracellular components. In this narrative review, we provide a comprehensive overview of autophagy's cellular and molecular basis, biological significance, pharmacological modulation, and its relevance in lifestyle medicine. We delve into the intricate molecular mechanisms that govern autophagy, including macroautophagy, microautophagy and chaperone-mediated autophagy. Moreover, we highlight the biological significance of autophagy in aging, immunity, metabolism, apoptosis, tissue differentiation and systemic diseases, such as neurodegenerative or cardiovascular diseases and cancer. We also discuss the latest advancements in pharmacological modulation of autophagy and their potential implications in clinical settings. Finally, we explore the intimate connection between lifestyle factors and autophagy, emphasizing how nutrition, exercise, sleep patterns and environmental factors can significantly impact the autophagic process. The integration of lifestyle medicine into autophagy research opens new avenues for promoting health and longevity through personalized interventions.

Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities.

Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO43- and ionized calcium (Ca2+). It is a crucial process in the development of bones and teeth. However, pathological calcification can occur in almost any soft tissue of the organism. The better studied is vascular calcification, where calcium salts can accumulate in the intima or medial layer or in aortic valves, and it is associated with higher mortality and cardiovascular events, including myocardial infarction, stroke, aortic and peripheral artery disease (PAD), and diabetes or chronic kidney disease (CKD), among others. The process involves an intricate interplay of different cellular components, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and pericytes, concurrent with the activation of several signaling pathways, calcium, Wnt, BMP/Smad, and Notch, and the regulation by different molecular mediators, growth factors (GFs), osteogenic factors and matrix vesicles (MVs). In the present review, we aim to explore the cellular players, molecular pathways, biomarkers, and clinical treatment strategies associated with vascular calcification to provide a current and comprehensive overview of the topic.

Connecting epigenetics and inflammation in vascular senescence: state of the art, biomarkers and senotherapeutics.

Vascular diseases pose major health challenges, and understanding their underlying molecular mechanisms is essential to advance therapeutic interventions. Cellular senescence, a hallmark of aging, is a cellular state characterized by cell-cycle arrest, a senescence-associated secretory phenotype macromolecular damage, and metabolic dysregulation. Vascular senescence has been demonstrated to play a key role in different vascular diseases, such as atherosclerosis, peripheral arterial disease, hypertension, stroke, diabetes, chronic venous disease, and venous ulcers. Even though cellular senescence was first described in 1961, significant gaps persist in comprehending the epigenetic mechanisms driving vascular senescence and its subsequent inflammatory response. Through a comprehensive analysis, we aim to elucidate these knowledge gaps by exploring the network of epigenetic alterations that contribute to vascular senescence. In addition, we describe the consequent inflammatory cascades triggered by these epigenetic modifications. Finally, we explore translational applications involving biomarkers of vascular senescence and the emerging field of senotherapy targeting this biological process.

Exploring Biomarkers in Breast Cancer: Hallmarks of Diagnosis, Treatment, and Follow-Up in Clinical Practice.

Breast cancer is a prevalent malignancy in the present day, particularly affecting women as one of the most common forms of cancer. A significant portion of patients initially present with localized disease, for which curative treatments are pursued. Conversely, another substantial segment is diagnosed with metastatic disease, which has a worse prognosis. Recent years have witnessed a profound transformation in the prognosis for this latter group, primarily due to the discovery of various biomarkers and the emergence of targeted therapies. These biomarkers, encompassing serological, histological, and genetic indicators, have demonstrated their value across multiple aspects of breast cancer management. They play crucial roles in initial diagnosis, aiding in the detection of relapses during follow-up, guiding the application of targeted treatments, and offering valuable insights for prognostic stratification, especially for highly aggressive tumor types. Molecular markers have now become the keystone of metastatic breast cancer diagnosis, given the diverse array of chemotherapy options and treatment modalities available. These markers signify a transformative shift in the arsenal of therapeutic options against breast cancer. Their diagnostic precision enables the categorization of tumors with elevated risks of recurrence, increased aggressiveness, and heightened mortality. Furthermore, the existence of therapies tailored to target specific molecular anomalies triggers a cascade of changes in tumor behavior. Therefore, the primary objective of this article is to offer a comprehensive review of the clinical, diagnostic, prognostic, and therapeutic utility of the principal biomarkers currently in use, as well as of their clinical impact on metastatic breast cancer. In doing so, our goal is to contribute to a more profound comprehension of this complex disease and, ultimately, to enhance patient outcomes through more precise and effective treatment strategies.

Histopathological Clues of Enhanced Inflammation in the Placental Tissue of Women with Chronic Venous Disease in Lower Limbs during Pregnancy.

It is estimated that approximately one in three women develop chronic venous disease (CVD) during pregnancy, a broad spectrum of morphofunctional disorders affecting the venous system in different regions of the body, including the lower limbs. A growing body of evidence supports the diverse maternofetal consequences derived from this condition, with the placenta being an organ particularly affected. Among other consequences, having CVD during pregnancy has been associated with systemic inflammation and altered cytokines and chemokine profiles in the maternal and fetal serum related to this condition. In the present work, we aimed to analyze if these inflammatory changes also occurred in the placental tissue of women with CVD, exploring by immunohistochemistry and real-time PCR (RT-qPCR) gene and protein expression of critical inflammatory markers like allograft inflammatory factor 1 (AIF-1), interleukin 10 (IL-10), IL-12A, and IL-18. Our results demonstrate an enhanced tissue expression of AIF-1, IL-12A, and IL-18, accompanied by a decrease in IL-10 in the placentas of women who had undergone CVD during pregnancy. Overall, our results suggest a possible pathophysiological role of inflammation in the placental tissue of women with CVD during pregnancy, although the precise consequences of this feature remain to be deeply analyzed.

Elevated tissue expression of RANKL and RANK is associated with poorer survival rates in pancreatic cancer patients.

Pancreatic cancer is a highly lethal malignancy with a growing incidence reported worldwide. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, which is often diagnosed at advanced stages, making its prognosis and medical management difficult. The identification of histopathological biomarkers has allowed a more precise stratification of pancreatic cancer patients, providing additional information about their prognosis and offering possible therapeutic targets to be explored. The prognostic value of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) has been evaluated in breast and prostate tumors, however, their usefulness has not been assessed in pancreatic cancer. In the present work, we analyzed the relationship between the protein expression of RANK and RANKL with the survival of 41 patients with pancreatic cancer followed for 60 months, by performing immunohistochemistry and Kaplan-Meier curves. Our results demonstrate a direct association of high expression levels of RANK and RANKL with poorer survival of pancreatic cancer patients in comparison to those with low/medium and null expression levels of both markers. Further studies should be conducted to explore the carcinogenic role of both components in this type of tumor, as well as additional promising translational uses.

Análisis del índice de consecución de residencia pública asistida tras ingreso hospitalario en ancianos frágiles / Analysis of placement in public nursing homes after hospital admission in the fragile elderly

Introducción Analizar el índice de consecución de plaza en residencia pública asistida (RPA) en ancianos hospitalizados y orientados a este recurso por la Unidad de Trabajo Social.Material y métodos Estudio de cohortes realizado en una unidad de agudos de Geriatría de un hospital terciario. Se estudian los datos demográficos, clínicos, funcionales y socioeconómicos registrados en el ingreso hospitalario (período de inclusión de 4 años). Seguimiento al alta durante 6 meses, determinando porcentaje de consecución de RPA, tiempo de espera (tasa de incidencia mensual) y causas de no consecución. Las variables que se asocian a la consecución de RPA se introducen en un modelo de regresión logística multivariado.Resultados Cuatrocientos quince ancianos orientados a RPA, edad de 85,1 años (DE=6,7), 61,9% de mujeres. En el período de seguimiento obtuvieron plaza 72 ancianos (17,3%; tasa de incidencia mensual: 3,14%). En el análisis multivariado vivir solo (odds ratio [OR]: 2,788; p=0,005), recibir menos ingresos (OR: 0,807; p=0,018), tener informe de derivación social desde el hospital (OR: 2,132; p=0,037), haber solicitado RPA previamente (OR: 3,298; p=0,002) y ubicación al alta hospitalaria diferente al domicilio (OR: 5,792; p<0,001) se asociaron de modo independiente a consecución de RPA. Fallecer en espera (41,4%) y no finalizar trámites (32,9%) fueron las causas fundamentales de no consecución de plaza.Conclusiones La hospitalización de pacientes ancianos frágiles conduce frecuentemente a la solicitud de RPA, aunque su consecución a corto plazo desde la unidad de agudos es escasa. Determinados factores socioeconómicos y la intervención social facilitan el acceso, aunque la espera condiciona una importante proporción de fallecimientos e interrupción de trámites debido, en gran medida, a la complejidad del proceso (AU)

Introduction To analyze placement in public nursing homes in elderly inpatients referred by the social work unit. Material and methods We performed a cohort study in an acute geriatric unit of a tertiary hospital. The sociodemographic, clinical, functional and socioeconomic data registered on admission (inclusion period: 4 years) were analyzed. The patients were followed-up for 6 months after discharge. The percentage gaining places in public nursing homes, the waiting time (monthly incidence rate) and the reasons for not gaining a place were evaluated. The variables associated with gaining a place were introduced into a multivariate logistic regression model. Results A total of 415 elders were referred to public nursing homes. The mean age was 85.1 years (SD=6.7), and 61.9% were women. During the follow-up period, 72 elders were granted a place (17.3%; monthly incidence rate 3.14%). In the multivariate analysis, the factors independently associated with gaining a place at a public nursing home were living alone (OR 2.788; p=0.005), having a lower income (OR 0.807; p=0.018), having a social work report from the hospital (OR 2.132; p=0.037), having previously requested a place at a public nursing home (OR 3.298; p=0.002) and discharge destination other than the home (OR 5.792; p<0.001). The main causes associated with not gaining a place were death while on the waiting list (41.4%) and not completing the paperwork (32.9%). ConclusionsHospitalization in the frail elderly frequently leads to requests for public nursing home admission, although few places are granted in the short term to patients in the acute unit. Certain socioeconomic factors and referral by social workers were positively associated with gaining a place. However, the waiting time leads to a substantial proportion of deaths and incomplete paperwork, largely due to the complexity of the process (AU)

Análisis de mortalidad tras el ingreso en una unidad de agudos de geriatría: influencia de la dependencia funcional / Analysis of mortality after admission to an acute geriatric unit: influence of functional dependency

Objetivo: analizar la influencia de diversos factores clínicos y funcionales en la tasa de mortalidad anual tras ingreso en unidad de agudos de geriatría (UGA). Material y métodos: pacientes ingresados durante 6 meses en la UGA. Se excluyeron los ingresos inadecuados o trasladados a otro servicio en el primer día. Para la valoración clínica, funcional y psíquica basal se utilizaron los índices de Katz y de Barthel, la escala de la Cruz Roja física y la presencia de demencia. Los datos al ingreso: mortalidad, complicaciones, impacto funcional del ingreso. En el seguimiento al año se analizaron los datos de mortalidad cruda y comorbilidad (índice de Charlson [ICh]). Se analizó la influencia de los datos basales y del ingreso en la supervivencia. El análisis estadístico se realizó mediante la comparación de medias y proporciones mediante las pruebas de la χ2, de la t de Student y ANOVA de un factor. El estudio de supervivencia se realizó mediante curvas de Kaplan-Meier y regresión de Cox, con un intervalo de confianza del 95%. Se utilizó el programa SPSS 11.0 para el procesamiento estadístico de los datos. Resultados: se analizó a 336 pacientes, con una edad media ± desviación estándar de 85,6 ± 6,9 años; el 59,2% eran mujeres. El grupo relacionado de diagnóstico principal fue de 541. Datos basales: demencia moderada o grave, 39,3%; dependencia en más de 3 actividades básicas, 45,4%; movilidad restringida, 48,2%, e incontinencia funcional, 29,9%. Datos del ingreso: impacto funcional, 19,5%, e infección nosocomial, 47,6%. La mortalidad intrahospitalaria fue del 22,9%. Durante el seguimiento hubo un 5,1% de pérdidas. Al año fallecieron 107 pacientes más (total 184; 54,8%). La mitad de los fallecimientos se produjo en los primeros 59 días contados desde el día del ingreso. Mediana de supervivencia, 275 días. Comorbilidad ICh > 2 (47,6%). Las causas de defunción fueron: en el 37,5% de los casos, respiratoria, y en el 31,0% de los pacientes, circulatoria. Los factores relacionados con la mortalidad fueron: sexo varón (p = 0,029), demencia (p = 0,002), pérdida funcional (p < 0,001), infección respiratoria nosocomial (p = 0,026), cuadro confusional (p < 0,001) y comorbilidad (p = 0,015); no se encontró asociación con la edad u otros factores clínicos. En el modelo de regresión de Cox, únicamente ser varón (p = 0,021) y la pérdida funcional asociada al ingreso (p < 0,001) se asociaron a mortalidad en el seguimiento. Conclusiones: se observó una elevada mortalidad durante los primeros dos meses desde el ingreso hospitalario, sobre todo por afección respiratoria y circulatoria. Aunque el sexo se asocia con la mortalidad en el seguimiento, ésta depende en mayor medida de la situación funcional. Se hace necesario establecer estrategias preventivas o de intervención en determinados grupos de ancianos de riesgo en los que es previsible una elevada mortalidad

Objective: to analyze the influence of several clinical and functional factors on the annual mortality rate following admission to an acute geriatric unit (AGU). Material and methods: patients admitted to the AGU over a 6-month period were included. Inappropriate admissions and those transferred to another service within 24 hours were excluded. Clinical, functional and psychic evaluations (Katz index, Barthel index, Physical Red Cross scale, presence of dementia) were performed. Admission data: mortality, complications, functional impact of admission. Follow-up at 1 year: data on crude mortality and comorbidity (Charlson index). The influence of baseline data and of admission on survival was analyzed. The statistical analysis consisted of comparison of means and proportions through the chi-squared test, Student's t-test and one-way ANOVA. Survival was studied through Kaplan-Meier curves and Cox regression. A 95% confidence interval was used. Data were analyzed with the SPSS 11.0 statistical package. Results: there were 336 patients (mean age 85.6 years; SD 6.9); 59.2% were women. Main diagnosis-related group: 541. Baseline data: moderate or severe dementia was found in 39.3%, dependency for more than three basic activities of daily living in 45.4%, restricted mobility in 48.2%, and functional incontinence in 29.9%. Admission data: functional impact was found in 19.5% and nosocomial infection in 47.6%. In-hospital mortality: 22.9%. Follow-up: 5.1% were lost to follow-up. At 1 year a further 107 patients had died (total 184; 54.8%). Half of the deaths occurred in the first 59 days after admission. The median survival was 275 days. The Charlson comorbidity index score was >2: 47.6%. Causes of death were respiratory in 37.5% and circulatory in 31.0%. The factors related to mortality were male sex (P=.029), dementia (P =.002), functional loss (P<.001), nosocomial respiratory infection (P =.026), confusional syndrome (P<.001), and comorbidity (P =.015). No association was found with age or other clinical factors. In the Cox regression model, only male sex (P=.021) and functional loss associated with admission (P<.001) were related to mortality during follow-up. Conclusions: mortality was high during the first 2 months after hospital admission, especially that due to respiratory and circulatory disease. Although sex was associated with mortality during follow-up, mortality was to a greater extent due to functional status. Preventive strategies and/or interventions are required in specific groups of elderly patients with an elevated risk of mortality

Actividad de la tiopurina metiltransferasa en la enfermedad inflamatoria intestinal. Un estudio en 7.046 pacientes españoles / Thiopurine methyltransferase activity in the inflammatory bowel disease. A study on 7046 Spanish patients

Fundamento y objetivo: El objetivo del presente estudio es describir la actividad enzimática de la tiopurina metiltransferasa (TPMT) en un grupo muy numeroso de pacientes españoles con enfermedad inflamatoria intestinal (EII), evaluar el efecto de algunas variables sobre dicha actividad y conocer la proporción de pacientes con baja actividad y, por tanto, mayor riesgo de mielotoxicidad por azatioprina/6-mercaptopurina. Pacientes y método: Se determinó la actividad de TPMT mediante un método radioquímico en pacientes con EII. La asociación entre diversas variables y la actividad de TPMT se estudió mediante regresión lineal múltiple. Resultados: Se incluyó a 7.046 pacientes, el 70% con enfermedad de Crohn, el 22% con colitis ulcerosa y un 8% con colitis indeterminada. El valor medio de TPMT fue de 20 U/ml (extremos: 0-46). La distribución de actividad de TPMT fue: un 0,5% con valores bajos (= 13,8). Los valores de TPMT no siguieron una distribución normal (p < 0,001). En el estudio univariante se demostraron diferencias estadísticamente significativas (p < 0,001), aunque de dudosa relevancia clínica al ser mínimos, en los valores de TPMT en función de la edad, el sexo, el tipo de enfermedad y el tratamiento con azatioprina/6-mercaptopurina. En el estudio multivariante, el sexo y el tratamiento con 5-aminosalicilatos, glucocorticoides y azatioprina/6-mercaptopurina se asoció significativamente con la actividad de TPMT. Conclusiones: El 0,5% de los pacientes españoles con EII tiene una baja actividad enzimática de TPMT (< 5 U/ml, lo que indica un mayor riesgo de mielotoxicidad por azatioprina/6-mercaptopurina), una cifra similar a la descrita en otros países. Los diversos fármacos empleados en el tratamiento de la EII, como los 5-aminosalicilatos o la azatioprina/6-mercaptopurina, no parecen modificar de forma clínicamente relevante dicha actividad enzimática

Background and objective: Our objective was to assess the activity of thiopurine methyltransferase (TPMT) in a very large number of Spanish patients with inflammatory bowel disease (IBD), to evaluate the influence of several variables (including azathioprine or 6-mercaptopurine) on that activity, and to know the proportion of patients with low TPMT activity and therefore high risk of myelotoxicity when treated with these drugs. Patients and method: TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several variables and TPMT values was assessed by multiple lineal regression. Results: 7046 patients were included (mean age: 37 years; 53% males): 70% with Crohn's disease, 22% with ulcerative colitis, and 8% with indeterminate colitis. Mean TPMT value was 20 (6) U/ml RBCs (minimum 0 and maximum 46). TPMT activity distribution was as follows: low levels (= 13.8), 88.4%. TPMT values did not follow a normal distribution (p < 0.001). In the univariate study, statistically significant differences (p < 0.001), yet of doubtly clinical significance because its minimal magnitude, were demonstrated in TPMT values depending on age, sex, type of disease, and treatment with azathioprine/6-mercaptopurine. In the multivariate study, the variables associated with TPMT activity were: sex, treatment with 5-aminosalicylates, steroids and azathioprine/6-mercaptopurine. Conclusions: This study shows that 0.5% of the Spanish patients with IBD have low TPMT activity (< 5 U/ml RBCs), a figure similar to that reported in other countries, these patients being at higher risk of myelotoxicity when treated with azathioprine or 6-mercaptopurine. The drugs usually prescribed for the treatment of IBD, including 5-aminosalicylates and azathioprine/6-ercaptopurine, do not seem to modify in a clinically relevant manner TPMT activity

Actividad de la tiopurina metiltransferasa en pacientes con hepatitis autoinmune / Thiopurine methyltransferase activity in patients with autoimmune hepatitis

FUNDAMENTO Y OBJETIVO: La determinación de la actividad de la tiopurina metiltransferasa (TPMT) sirve para controlar de forma individualizada la dosis de azatioprina con la intención de identificar a los pacientes con riesgo de mielotoxicidad, pero la distribución de la actividad enzimática en los pacientes con hepatitis autoinmune en concreto se desconoce. Nuestro objetivo fue describir la actividad de la TPMT en un grupo de más de 200 pacientes con hepatitis autoinmune y evaluar el posible efecto de algunas variables (entre las que destaca el tratamiento con azatioprina) sobre dicha actividad. PACIENTES Y MÉTODO: Se determinó, mediante un método radioquímico, la actividad de la TPMT en los eritrocitos de pacientes con hepatitis autoinmune procedentes de 31 hospitales españoles. Se estudió la relación entre los valores de TPMT y diversas variables demográficas, así como su correlación con el tratamiento con azatioprina. RESULTADOS: Se incluyeron 209 pacientes (80 por ciento mujeres, edad media de 50 años, el 39 por ciento recibía azatioprina). El valor medio de TPMT fue de 20,7 U/ml hematíes (mínimo de 0 y máximo de 39). Los valores de TPMT se ajustaron a una distribución normal. La proporción de pacientes con TPMT con valores bajos (< 5 U/ml), intermedios (5-13,7 U/ml) y altos ( 13,8 U/ml) fue, respectivamente, del 1, 9 y el 90 por ciento. En el análisis multivariante no se demostraron diferencias al comparar los valores medios de TPMT en función de la edad, el sexo o el tratamiento previo con azatioprina. CONCLUSIONES: La actividad de la TPMT en los pacientes con hepatitis autoinmune sigue una distribución semejante a la descrita en otras poblaciones (esto es, aproximadamente un 1 por ciento de los pacientes tiene valores bajos y un 9 por ciento, intermedios) y no depende de la edad, del sexo ni del tratamiento concomitante con azatioprina. (AU)

Actividad de la tiopurina metiltransferasay mielotoxicidad debida a azatioprina y 6-mercaptopurinaen pacientes con enfermedad inflamatoria del intestino / Thiopurine methyltransferase activity and myelosuppression in inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine

FUNDAMENTO Y OBJETIVO: Evaluar si existe una relación entre la actividad de la tiopurina metiltransferasa (TPMT) y la incidencia de efectos adversos, especialmente mielotoxicidad, en los pacientes con enfermedad inflamatoria del intestino tratados con azatioprina (AZA) o 6-mercaptopurina (6-MP).PACIENTES Y MÉTODO: Se determinó mediante un método radioquímico la actividad de TPMT en los eritrocitos de pacientes con enfermedad inflamatoria del intestino que habían recibido o estaban recibiendo tratamiento con AZA o 6-MP (n = 97) y en los que no habían sido tratados nunca con dichos fármacos (n = 37). Se estudió la relación entre diversas variables y los valores de TPMT, y se evaluó la correlación entre estos valores y la incidencia de efectos adversos. RESULTADOS: El valor medio (DE) de TPMT fue de 20,8 (5) U/ml hematíes (mínimo, 7,8; máximo, 32,7). No hubo ningún paciente con valores bajos (inferiores a 5 U/ml) de TPMT, el 9 por ciento tuvo concentraciones intermedias (entre 5 y 13,7 U/ml), y en el 91 por ciento se evidenciaron concentraciones elevadas (iguales o mayores de 13,8 U/ml). No se demostraron diferencias al comparar los valores de TPMT en función de las diversas variables consideradas (edad, sexo, tabaco, peso, tipo de enfermedad inflamatoria del intestino, tratamiento con 5-aminosalicilatos, esteroides o AZA/6-MP). Se describieron efectos adversos en 13 de los 97 pacientes (13 por ciento) que recibían AZA/6-MP (neutropenia en el 1 por ciento y pancitopenia en el 3 por ciento). Ninguno de los pacientes con efectos adversos tuvo concentraciones de TPMP anormalmente bajas (inferiores a 5 U/ml), ni siquiera intermedias (5-13,7 U/ml). No se demostraron diferencias al comparar los valores medios de TPMT entre los pacientes que refirieron efectos secundarios y los que no, tanto en general como al considerar la mielotoxicidad en concreto. CONCLUSIONES: En este estudio no se ha podido confirmar la utilidad de la determinación de la actividad de la TPMT para identificar a los pacientes con enfermedad inflamatoria del intestino y riesgo de mielotoxicidad debida a AZA o 6-MP. Los controles analíticos periódicos deben seguir realizándose en estos pacientes a pesar de que la actividad enzimática de la TPMT sea normal (AU)