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1.
Crit Rev Oncol Hematol ; 180: 103860, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36265547

RESUMEN

We performed a systematic review of phase I trials specifically designed for lymphoma patients. PubMed and Cochrane Library databases were searched using (lymphoma*) AND (phase 1) and publication date 2015-2020 to identify phase I dose-finding trials including a majority of lymphoma patients. Eighty-two trials (n = 3289 lymphoma patients) were included: 46 (55%) enrolled only lymphoma patients, 34 (41%) included also other hematologic malignancies, 2 (2%) solid tumors. Forty-six trials (56%) evaluated a combination (in 25 addition of experimental drug to standard therapy). Seven trials (9%) enrolled untreated patients. Among trials reporting activity in lymphoma patients, 74% (n = 57) reported an overall response rate ≥ 30%. All trials reported grade ≥ 3 adverse events; however, rates were not comparable across trials. Thirty-one treatment-related deaths in lymphoma patients were reported (overall treatment-related grade 5 adverse events rate 0.94%). Phase I trials designed for lymphoma patients were generally safe and the majority reported overall response rate ≥ 30%.


Asunto(s)
Linfoma , Humanos , Linfoma/tratamiento farmacológico , Ensayos Clínicos Fase I como Asunto
2.
Drug Resist Updat ; 55: 100744, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33551306

RESUMEN

Ovarian cancer is the fifth cause of cancer-related deaths in women with high grade serous carcinoma (HGSOC) representing the most common histological subtype. Approximately 50 % of HGSOC are characterized by deficiency in homologous recombination (HR), one of the main cellular pathways to repair DNA double strand breaks and one of the well-described mechanisms is the loss of function of the BRCA1 or BRCA2 genes. Inhibition of the poly-ADP-ribose polymerase (PARP) is synthetic lethal with HR deficiency and the use of PARP inhibitors (PARPi) has significantly improved the outcome of patients with HGSOC with a greater benefit in patients with BRCA1/2 deficient tumors. However, intrinsic or acquired resistance to PARPi inevitably occurs in most HGSOC patients. Distinct heterogeneous mechanisms underlying the resistance to PARPi have been described, including a decrease in intracellular drug levels due to upregulation of multidrug efflux pumps, loss of expression/inactivating mutations in the PARP1 protein, restoration of HR and the protection of the replicative fork. Deciphering the molecular mechanisms of resistance to PARPi is of paramount importance towards the development of new treatment strategies and/or novel pharmacological agents to overcome this chemoresistance and optimize the treatment regimen for individual HGSOC patients. The current review summarizes the mechanisms underlying the resistance to PARPi, the available preclinical and clinical data on new combination treatment strategies (with chemotherapy, anti-angiogenic agents and immune checkpoint inhibitors) as well as agents under investigation which target the DNA damage response.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína BRCA2/genética , Daño del ADN/efectos de los fármacos , Reparación del ADN/fisiología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba/fisiología
3.
Ann Oncol ; 28(9): 2206-2212, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-28911070

RESUMEN

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Quimioterapia de Inducción , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Quimioradioterapia , Cisplatino/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello , Análisis de Supervivencia , Taxoides/administración & dosificación
4.
Leukemia ; 30(9): 1805-15, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27389058

RESUMEN

The acquisition of a complete neoplastic phenotype requires cancer cells to develop escape mechanisms from the host immune system. This phenomenon, commonly referred to as 'immune evasion,' represents a hallmark of cancers and results from a Darwinian selection of the fittest tumor clones. First reported in solid tumors, cancer immunoescape characterizes several hematological malignancies. The biological bases of cancer immunoescape have recently been disclosed and include: (i) impaired human leukocyte antigen-mediated cancer cell recognition (B2M, CD58, CTIIA, CD80/CD86, CD28 and CTLA-4 mutations); (ii) deranged apoptotic mechanisms (reduced pro-apoptotic signals and/or increased expression of anti-apoptotic molecules); and (iii) changes in the tumor microenvironment involving regulatory T cells and tumor-associated macrophages. These immune-escape mechanisms characterize both Hodgkin and non-Hodgkin (B and T cell) lymphomas and represent a promising target for new anti-tumor therapies. In the present review, the principles of cancer immunoescape and their role in human lymphomagenesis are illustrated. Current therapies targeting these pathways and possible applications for lymphoma treatment are also addressed.


Asunto(s)
Sistema Inmunológico/inmunología , Linfoma/patología , Escape del Tumor , Humanos , Linfoma/inmunología , Macrófagos/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología
5.
Ann Oncol ; 27(6): 1123-1128, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26961147

RESUMEN

BACKGROUND: Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models. MATERIALS AND METHODS: Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed. RESULTS: Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib. CONCLUSION: The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Linfoma de Células B/tratamiento farmacológico , Niacinamida/análogos & derivados , Proteínas Tirosina Quinasas/genética , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Animales , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/genética , Ratones , Terapia Molecular Dirigida , Niacinamida/administración & dosificación , Piperidinas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Quinazolinonas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Ann Oncol ; 26(11): 2317-22, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26362567

RESUMEN

BACKGROUND: This study was aimed at investigating the clinical features and outcomes of follicular lymphoma (FL) patients younger than 40 years, which have not been extensively investigated yet. PATIENTS AND METHODS: One hundred and fifty-five patients younger than 40 years were retrospectively studied from a series of 1002 FL patients diagnosed in four different European Oncology Centres (Barcelona, Spain; Bellinzona, Switzerland; London, UK; Novara, Italy) from 1985 to 2010. RESULTS: Patients younger than 40 had a lower incidence of elevated LDH, high beta2-microglobulin, and a high-risk Follicular Lymphoma International Prognostic Index (FLIPI) score, whereas bone marrow involvement and bulky and disseminated lymphadenopathy were more frequent. At a median follow-up of 10 years, younger patients, in comparison with those older than 40, had significantly better overall (OS), cause-specific survival (CSS), and progression-free survival (PFS), with 10-year OS rate of 81% versus 51% (P < 0.0001), 10-year CSS rate of 82% versus 60% (P < 0.0001), and 10-year PFS of 39% versus 24% (P = 0.0098). However, there were no significant CSS and PFS differences in comparison with the patients aged 40-60. In multivariate analysis, having the lymphoma diagnosed in the last two decades and a favourable FLIPI score were associated with a significantly longer PFS and CSS in younger patients, whereas only FLIPI retained statistical significance for OS. CONCLUSIONS: In our series, FL patients younger than 40 have a median OS of 24 years and their outcome seems to be improving over time. However, they still have a significantly shorter life expectancy than that of an age-matched general healthy population.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Esperanza de Vida/tendencias , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/epidemiología , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Italia/epidemiología , Londres/epidemiología , Linfoma Folicular/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , España/epidemiología , Suiza/epidemiología , Adulto Joven
7.
Ann Oncol ; 26(11): 2329-35, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26400898

RESUMEN

BACKGROUND: Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of MZL patients. PATIENTS AND METHODS: The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs [mucosa-associated lymphoid tissue (MALT) lymphoma, 46%], 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ). RESULTS: With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases [3.8%, 95% confidence interval (95% CI) 2%-6.5%]. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3-9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%-20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%-86%). CONCLUSIONS: In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.


Asunto(s)
Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B de la Zona Marginal/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Adulto Joven
8.
Cancer Invest ; 33(6): 232-40, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25950849

RESUMEN

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.


Asunto(s)
Algoritmos , Inteligencia Artificial , Metástasis Linfática/diagnóstico , Pelvis/patología , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Árboles de Decisión , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Sensibilidad y Especificidad
9.
Ann Oncol ; 26(6): 1069-1080, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25605746

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%-40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL.


Asunto(s)
Biomarcadores de Tumor/genética , Linfoma de Células B Grandes Difuso/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Terapia Molecular Dirigida , Farmacogenética , Fenotipo , Medicina de Precisión , Valor Predictivo de las Pruebas , Inducción de Remisión , Factores de Riesgo , Resultado del Tratamiento
11.
Leukemia ; 29(6): 1390-401, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25533804

RESUMEN

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.


Asunto(s)
Resistencia a Antineoplásicos , Linfoma Anaplásico de Células Grandes/genética , FN-kappa B/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Factor 1 Asociado a Receptor de TNF/genética , Translocación Genética/genética , Quinasa de Linfoma Anaplásico , Animales , Western Blotting , Citometría de Flujo , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunoprecipitación , Hibridación Fluorescente in Situ , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/mortalidad , Ratones , Ratones Endogámicos NOD , FN-kappa B/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Inhibidores de Proteasoma/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Factor 1 Asociado a Receptor de TNF/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Leukemia ; 28(6): 1334-40, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24296945

RESUMEN

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.


Asunto(s)
Biomarcadores de Tumor/genética , Diferenciación Celular , Exoma/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/patología , Mutación/genética , Neoplasias del Bazo/genética , Neoplasias del Bazo/patología , Ensamble y Desensamble de Cromatina , Citoesqueleto , Humanos , FN-kappa B/genética , Transducción de Señal
13.
Ann Oncol ; 24(5): 1378-84, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23372049

RESUMEN

BACKGROUND: Genomic complexity can predict the clinical course of patients affected by chronic lymphocytic leukemia (CLL) with a normal FISH. However, large studies are still lacking. Here, we analyzed a large series of CLL patients and also carried out the so far largest comparison of FISH versus single-nucleotide polymorphism (SNP) array in this disease. PATIENTS AND METHODS: SNP-array data were derived from a previously reported dataset. RESULTS: Seventy-seven of 329 CLL patients (23%) presented with a normal FISH. At least one large (>5 Mb) genomic aberration was detected by SNP array in 17 of 77 patients (22%); this finding significantly affected TTT. There was no correlation with the presence of TP53 mutations. In multivariate analysis, including age, Binet stage, IGHV genes mutational status and large genomic lesion, the latter three factors emerged as independent prognosticators. The concordance between FISH and SNP array varied between 84 and 97%, depending on the specific genomic locus investigated. CONCLUSIONS: SNP array detected additional large genomic aberrations not covered by the standard FISH panel predicting the outcome of CLL patients.


Asunto(s)
Aberraciones Cromosómicas , Leucemia Linfocítica Crónica de Células B/genética , Femenino , Genotipo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Análisis Multivariante , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Pronóstico , Proteína p53 Supresora de Tumor/genética
14.
Ann Oncol ; 23(3): 729-735, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21693768

RESUMEN

BACKGROUND: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 13/genética , Perfilación de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa
15.
Fish Shellfish Immunol ; 30(2): 609-17, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21168509

RESUMEN

Cellular and molecular data have evidenced a gut-associated lymphoid tissue in a variety of teleost species, abundantly containing T cells, whose origin, selection and functions are still unclear. This study reports CD4, CD8-α, MHCI-α, MHCII-ß, rag-1 and TCR-ß gene transcription along the intestine (anterior, middle and posterior segments) and in the thymus of one year-old Dicentrarchus labrax (L.). Real-time PCR findings depicted a main role of the thymus in T-cell development, but also rag-1 and CD8-α transcripts are detected in the intestine, having significant expression in the posterior segment. In the whole intestine TCR-ß and CD8-α exceeded CD4 transcripts. RNA ISH confirmed these data and detailed that mucosal CD8-α+ cells were especially numerous in the epithelium and in aggregates in the lamina propria. Regional differences in T-cell-specific gene expressions are first described in the intestine of a bony fish. High non-specific cytotoxic activity against xenogeneic and allogeneic cells was found in lymphocytes purified from the intestinal mucosa, providing further insight into their local defence roles.


Asunto(s)
Lubina/inmunología , Regulación de la Expresión Génica/inmunología , Intestinos/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD4/genética , Pruebas Inmunológicas de Citotoxicidad , Perfilación de la Expresión Génica , Genes MHC Clase II/genética , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T/genética , Reacción en Cadena de la Polimerasa , Timo/inmunología
16.
Mol Hum Reprod ; 16(7): 481-91, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20231161

RESUMEN

Cyclic adenosine 3'-5'-monophosphate (cAMP) is a second messenger, which exerts an important role in the control of human first-trimester trophoblast functions. In the present study we demonstrate the existence of a mechanism that is able to extrude cAMP from trophoblast-derived cell lines, and show evidence indicating the involvement of multidrug resistance protein (MRP) 1, a transporter belonging to the ATP-binding cassette family, in cAMP egress. MRP1 is expressed in trophoblast cell lines and cAMP efflux is highly reduced by the MRP1 inhibitor, MK-571. In addition, interleukin-1beta and estrone are able to enhance MRP1 gene expression and influence extracellular cAMP concentration. The occurrence of a MRP1-dependent cAMP efflux is also shown in human first-trimester placenta explants. Extracellular cAMP could represent a source for adenosine formation, which in turn could regulate cAMP-dependent responses in placental tissue. Evidence is provided that adenosine receptor subtypes are present and functional in human trophoblast-derived cells. A role for cAMP egress mechanism in the fine modulation of the nucleotide homeostasis is therefore suggested.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , AMP Cíclico/metabolismo , Trofoblastos/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Línea Celular Tumoral , Células Cultivadas , Colforsina/farmacología , Estrona/farmacología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas In Vitro , Interleucina-1beta/farmacología , Placenta/metabolismo , Embarazo , Probenecid/farmacología , Progesterona/farmacología , Propionatos/farmacología , Quinolinas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trofoblastos/efectos de los fármacos
17.
Leukemia ; 23(6): 1118-26, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19448608

RESUMEN

Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P=0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P=0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P=0.018), infectious (OR: 0.46; P=0.003) and cardiac toxicity (OR: 0.37; P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glutatión Transferasa/genética , Linfoma de Células B Grandes Difuso/diagnóstico , NADPH Oxidasas/genética , Farmacogenética/métodos , Valor Predictivo de las Pruebas , Anciano , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Genotipo , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Prednisona/administración & dosificación , Pronóstico , Rituximab , Vincristina/administración & dosificación
18.
Hematol Oncol ; 27(3): 154-9, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19274614

RESUMEN

Mantle cell lymphoma (MCL) has a poor prognosis with often short and incomplete remissions. We aimed to test the efficacy and tolerability of gemcitabine in treating MCL. Gemcitabine was given in doses of 1000 mg/m(2) as a 30 min infusion on days 1 and 8 of each 3 week cycle for a maximum of nine cycles. Eighteen patients with a median age of 70 years were recruited. MCL was newly diagnosed in half of patients and relapsed in the remainder. Fifteen patients had Ann Arbor stage IV. The best-recorded responses were 1 CR (complete remission), 4 PRs (partial responses), 8 SDs (stable diseases) and 4 PDs (diseases progression). The response rate (RR) (CR + PR) was 5 (28%; 95% confidence interval: 7.1, 48.5). The patient achieving a CR had stage IV disease. Most haematological adverse events occurred during the first chemotherapy cycle. Three patients developed non-haematological serious adverse events: dyspnea, glomerular microangiopathy with haemolytic uremic syndrome (HUS) and hyperglycaemia. The median time-to-progression and treatment response duration (TRD) was 8.0 (95% confidence interval: 5.5, 9.3) and 10.6 (95% confidence interval: 5.5, 10.9) months, respectively. We conclude that Gemcitabine is well tolerated, moderately active and can induce disease stabilization in patients with MCL.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Linfoma de Células del Manto/tratamiento farmacológico , Anciano , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Femenino , Humanos , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Gemcitabina
19.
J Clin Pathol ; 62(2): 163-7, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19181633

RESUMEN

BACKGROUND: Gorham disease is a rare pathological condition characterised by a proliferation of vascular channels of haematic and lymphatic origin in bone and adjacent soft tissues, which results in a progressive destruction of the involved bone segment. AIM: To evaluate expression of the vascular endothelial cell marker CD105/endoglin in Gorham disease of bone. METHODS: An immunohistochemical analysis was conducted on four cases of Gorham disease of bone, and for comparison on eight cases of conventional haemangioma of bone and on normal fetal and adult bone tissue specimens. RESULTS: Diffuse and intense immunostaining of endothelial cells for CD105 was observed in the specimens of fetal bone in areas undergoing ossification and in the growth plate of young adults. In medullary bone, CD105 positivity was limited to sinusoids of haemopoietic marrow, while endothelial cells of capillaries and small arterioles and venules within fatty marrow were either negative or showed weak immunostaining. The mean percentage of positive vessels in Gorham disease was significantly higher than in osseous haemangioma (58.9 (SEM 14.9) vs 17.2 (SEM 12.0); p = 0.03, Mann-Whitney U test). A significant direct correlation was observed between the proliferative activity assessed by MIB-1 immunostaining, and the percentage of CD105 positive vessels in the entire series (r = 0.681; p = 0.01). CONCLUSIONS: Data indicate that the phenotype of proliferating endothelial cells of Gorham disease is similar to that of the endothelial lining of vessels of metabolically active bone characterised by high expression of CD105, while that of conventional haemangioma is more similar to that of metabolically quiescent bone tissue, such as fatty marrow, with low levels of expression of CD105. This may have potential therapeutic and diagnostic applications.


Asunto(s)
Antígenos CD/metabolismo , Osteólisis Esencial/metabolismo , Receptores de Superficie Celular/metabolismo , Adolescente , Biomarcadores/metabolismo , Neoplasias Óseas/metabolismo , Huesos/irrigación sanguínea , Huesos/embriología , Huesos/metabolismo , Proliferación Celular , Endoglina , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Femenino , Feto/metabolismo , Hemangioma/metabolismo , Humanos , Técnicas para Inmunoenzimas/métodos , Masculino , Persona de Mediana Edad , Osteólisis Esencial/diagnóstico por imagen , Osteólisis Esencial/patología , Radiografía , Adulto Joven
20.
Ann Oncol ; 20(6): 1086-93, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19193705

RESUMEN

BACKGROUND: Treatment aimed at eradicating Helicobacter pylori infection results in lymphoma remission in most localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas. The aim of this survey is to investigate the long-term effect of this therapeutic approach in a large series of patients. METHODS: One hundred and five patients with localized gastric MALT lymphoma were initially treated only with H. pylori eradication regimens. Lymphoma responses were graded using the Wotherspoon score. RESULTS: Helicobacter pylori, detected by histology in 81% of cases, was eradicated in all positive patients. Histological regression of the lymphoma was achieved in 78 of 102 assessable patients [76%, 95% confidence interval (CI): 67% to 84%] with complete remission (score 0-2) in 66 and partial remission (score 3) in 12. At a median follow-up time of 6.3 years, histological remission was consistently confirmed in 33 of 74 assessable patients, while 25 had score fluctuations (from 0 to 4) and 13 presented a lymphoma relapse (score 5). Only one patient had a distant progression. Transformation to a large-cell lymphoma was seen in two cases. The 5- and 10-year overall survival is 92% (95% CI: 84% to 96%) and 83% (95% CI: 70% to 91%), respectively. Only one patient died of lymphoma after transformation to a high-grade lymphoma. CONCLUSIONS: Helicobacter pylori eradication resulted in complete lymphoma remission in the majority of cases. Long-term clinical disease control was achieved in most patients. A watch and wait policy appears to be safe in patients with minimal residual disease or histological-only local relapse.


Asunto(s)
Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/microbiología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Neoplasias Gástricas/microbiología , Adulto Joven
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