RESUMEN
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) finely regulates both innate and adaptive immune responses through the degradation of the essential amino acid tryptophan into kynurenine and other downstream metabolites, which suppress effector T-cell function and promote the differentiation of regulatory T cells. A novel role for IDO1 as a signaling molecule and a modifier of innate inflammatory responses is now emerging. In particular, IDO1 can either support or antagonize inflammation in a context- and tissuedependent manner. Studies in experimental arthritis have unravelled a previously unappreciated role for IDO in controlling B-cell activation and autoantibody production. IDO dysregulation has been documented in patients with systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome, as well as in severe sepsis and chronic kidney disease. This article summarizes the contribution of IDO to the pathophysiology of inflammatory/autoimmune disorders, and discusses whether strategies to restore metabolic equilibrium in the kynurenine pathway might be pursued in diseases states such as rheumatoid arthritis and systemic sclerosis.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Enfermedades Reumáticas/tratamiento farmacológico , Animales , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/enzimología , Artritis Reumatoide/patología , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/patología , Enfermedades Reumáticas/enzimología , Enfermedades Reumáticas/patología , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/enzimología , Esclerodermia Sistémica/patología , Síndrome de Sjögren/tratamiento farmacológico , Síndrome de Sjögren/enzimología , Síndrome de Sjögren/patología , Triptófano/metabolismoRESUMEN
OBJECTIVES: BAFF and APRIL belong to the tumor necrosis factor (TNF) superfamily and are crucial for the survival, maturation, and differentiation of B cells. Aim of the study is to evaluate BAFF and APRIL in patients affected by Sjögren syndrome (SS) and systemic lupus erythematosus (SLE). METHODS: Sixty patients, (40 SLE, 20 SS) and 20 healthy subjects were enrolled in this study. All subjects were evaluated for laboratory data (ESR, CRP, immunoglobulin G, A and M, complement fragments C3 and C4, LDH, beta2microglobulin, serum levels of rheumatoid factor), autoantibodies (ANA; ENA-SSA, -SSB, -Sm) and lymphocytes subpopulations. For patients, disease activity and damage indexes were assessed with the use of SLEDAI and SLICC and SSDAI and SSDDI for SLE and SS, respectively. BAFF and APRIL were determined by commercial sandwich ELISA kit (R&D Systems, Bender MedSystem). Statistical analysis has been performed with software Prism (Graphpad Instat, version 5.00). RESULTS: APRIL levels were higher among SLE and SS patients compared to controls (p<0.0001, and p0.0001, respectively). BAFF levels in SLE were significantly higher than in SS (p<0.0001). We found higher BAFF levels in SLE and SS compared to controls (p<0.0001). Among SLE patients APRIL correlated with SLEDAI (r 0.3, p 0.04), SLICC (r 0.5,p 0.001), ESR (r 0.3, p 0.005) and CRP (r 0.4, p 0.02). Among SS patients APRIL correlated with SSDAI (r 0.4, p 0.02), SSDDI (r 0.4, p0.01), IgG (r 0.5, p0.01), ESR (r 0.6, p 0.01), CRP (r 0.6, p 0.02) and CD19 B lymphocytes absolute count (r 0.4, p 0.04); BAFF correlated with SSDDI (r 0.7, p 0.004) and CD19 B lymphocytes absolute count (r 0.5, p 0.04). CONCLUSIONS: In this study we showed a correlation between disease activity, damage indexes and BAFF/APRIL levels in SLE and SS patients suggesting a role in the strong activation of the immune system in patients with active disease.
Asunto(s)
Factor Activador de Células B/fisiología , Lupus Eritematoso Sistémico/etiología , Síndrome de Sjögren/etiología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/fisiología , Adulto , Enfermedad Crónica , Femenino , Humanos , Inflamación/etiología , Persona de Mediana EdadRESUMEN
Epithelial ovarian carcinoma represents a prototypic example of neoplastic disease sharing at the same time good chemosensitivity as well as marked propensity to relapse. If in one hand the definition of almost clear-cut guidelines has been reached in the setting of first-line therapy (i.e., cytoreductive surgery followed by first-line chemotherapy), more difficult to discern for the oncologist remains the choice of treatment in the occasion(s) of relapse(s). This article focuses on this particular setting of disease, analyzing the specific criteria of choice of drug or their combinations; the definite criteria followed for the use of platinum compounds in the second line of treatment, even if already utilized in the front line therapy, are also analyzed. Specific attention has also been paid in the definition of the role of single parameter as a "prognosticator" and/or as "predictor" of response. The Authors emphasize how clinical definitions remain the more reliable, simple, reproducible tools in therapeutical decision making.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Ca-125/sangre , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/sangre , PronósticoRESUMEN
PURPOSE: To evaluate the therapeutic activity and toxicity of gemcitabine in the treatment of metastatic urothelial carcinoma. PATIENTS AND METHODS: Twenty-four consecutive patients with recurrent- and/or metastatic urothelial carcinoma pretreated with first line cisplatin-based chemotherapy were treated with gemcitabine 1000 mg/m2/week intravenously diluted in 250 cc of normal saline as 20 minutes infusion for 3 consecutive weeks followed by a 1 week rest period. Chemotherapy was repeated every 28 days. RESULTS: All enrolled patients were evaluable for objective response accordingly to an intent-to-treat analysis. A complete response was achieved in 1 patient (4%) and a partial response in 6 cases (25%) for an overall response rate of 29% (confidence limits 18%-39%). The median duration of objective responses was 7.4+ months (range 3.0+/12.8). Six patients showed no changes (25%) with a median duration of 4.0 months. A subjective improvement in tumor-related symptoms was reported by all responding patients, and in 3 patients with no change. Six out of 9 patients with symptomatic bone lesions had a subjective improvement with reduction in analgesic drugs consumption. Objective responses were observed at all sites of disease. The median overall survival was 13.0+ months (range 4.0/16.2+). Over a total of 76 cycles (a mean of 3.1 cycles/patient), grade 1-2 leukopenia was seen in 9 patients (37%), grade 1-2 thrombocytopenia in 4 patients (17%), and grade 1 anemia in only 2 cases (8%). Grade 3 leukopenia was seen in 3 cases (12.5%). Grade 4 leukopenia or grade 3-4 thrombocytopenia were not seen. Gastrointestinal toxicity was very mild. CONCLUSIONS: Single agent gemcitabine at the dose of 1000 mg/m2 on a weekly schedule is active, at least in terms of objective response rate and tumor-related symptoms palliation, against pretreated urothelial carcinoma with good tolerability. These results compare favorably with those achieved with the most active drugs such as cisplatin and methotrexate.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias de la Vejiga Urinaria/cirugía , Urotelio/efectos de los fármacos , Desoxicitidina/uso terapéutico , Humanos , Metástasis de la Neoplasia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología , GemcitabinaRESUMEN
A case of primary liver cancer showing combined hepatocellular and cholangiocellular features and an associated pseudosarcomatous (schwannomatous) component is presented. Histologically, compact microtrabecular and glandular patterns in a dense fibrous stroma were recognized. The latter showed transition towards spindle cell sarcomatous growth in several areas of both the primary and the lymph-node metastasis. Glandular areas expressed acidic mucins and AE1-reactive keratins; albumin mRNA was detected by in situ hybridization in both trabecular and glandular areas. Vimentin and S-100 protein were mostly expressed in the pseudosarcomatous areas. Both the morphological patterns and the phenotypic features indicate that divergent differentiation along both epithelial and mesenchymal lineages took place in this rare primary liver tumor.
Asunto(s)
Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos , Conductos Biliares Intrahepáticos/patología , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Neoplasias Hepáticas/patología , Sarcoma/patología , Albúminas/análisis , Neoplasias de los Conductos Biliares/química , Conductos Biliares Intrahepáticos/química , Biomarcadores/análisis , Carcinoma Hepatocelular/química , Colangiocarcinoma/química , Resultado Fatal , Humanos , Inmunohistoquímica , Hibridación in Situ , Neoplasias Hepáticas/química , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Sarcoma/químicaRESUMEN
A detailed analysis of the immune system response has been performed during the development and progression of dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. For this aim, a number of immune parameters (thymocyte and splenocyte proliferative response to T-dependent mitogens, antibody production, lymphocyte subset phenotyping, interleukin 2 receptor expression in resting and activated lymphocytes, thymus morphology and morphometry), were correlated with tumor appearance and growth at different (-7, 0, +15, +30, +60, +90, and +120 days) time intervals after intragastric administration of DMBA, in the absence or the presence of a concomitant treatment with the thymic pentapeptide thymopentin (TP5). A profound and time-dependent immunosuppression characterized the treatment with the carcinogen. Both cell-mediated and humoral immune responses showed a 50% inhibition 2 weeks after DMBA administration, with a peak after 30 days, followed by a plateau until 120 days of observation. The mechanism responsible for reduced ability of thymocytes and splenocytes to respond to both Con-A and PHA was explained by the significant inhibition of one of the key steps of T cell activation, namely the expression of IL-2 receptor in lymphocytes from DMBA-treated animals. The flow cytometric analysis of lymphocyte subpopulations revealed an important reduction in the overall populations of thymocytes and splenocytes. At the thymus gland level, a dramatic reduction of double positive CD4+CD8+ and a decrease of CD4+CD8- and CD4-CD8+ were observed, together with a marked atrophy of the thymic cortex, and impairment of the thymic microenvironment. One hundred and twenty days after DMBA administration, approximately 60 to 70% of the animals developed tumors with a mean tumor surface area of 2.88 +/- 0.86 cm2, and a number of 2.44 +/- 1.0. Treatment with TP5 (100 ng/animal, three times a week, starting a week before DMBA), produced specific effects on different immune compartments and tumoral growth, characterized by a significant reversal of immune depression with a stimulatory effect measured on lymphoproliferative assays, lymphocyte subset distribution, and IL-2 receptor expression. Moreover, thymic atrophy was almost completely prevented in TP5 treated animals. Of major interest, a significant delay in the appearance and growth of tumors was observed in TP5 treated rats. When DMBA-treated animals were followed for the entire observation period (0-120 days) and the immune responsiveness correlated according to tumor progression, stability, or regression, a positive correlation was calculated between the degree of immune system depression and the individual rate of tumor growth; in TP5-treated rats the majority of the tumors were static or regressing tumors.(ABSTRACT TRUNCATED AT 400 WORDS)