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Prog. obstet. ginecol. (Ed. impr.) ; 62(3): 237-242, mayo-jun. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | ID: ibc-ET1-3620


Objective: The objective of our study was to identify prognostic factors, management strategies, and outcomes for locally advanced cervical cancer in our hospital. Material and methods: We performed a retrospective study of 156 patients with locally advanced cervical cancer (FIGO IB2-IVA). All patients underwent staging of the para-aortic lymph nodes by computed tomography. A total of 93 patients with para-aortic lymph nodes with no signs of malignancy in the imaging tests underwent pretherapy surgical staging up to the level of the left renal vein. All patients were treated with chemoradiation. Results: The study included a total of 156 patients. The average age was 54.04 years (range 28-97 years). Squamous cell carcinoma was the most frequent histological type (82.1%). Most patients had FIGO stage IIB disease (43.6%). Histopathology revealed metastatic disease in the para-aortic lymph nodes in 19.3% of patients. The status of the para-aortic lymph nodes was the only factor that was independently associated with an increased risk of mortality (OR 33 [95% CI, 8-135.89], p<0.0001). Conclusions: Patients with an advanced tumor stage at the time of diagnosis and those with pathological para-aortic lymph nodes are at greater risk of developing distant metastases and of more frequent disease-related mortality. In this group of high-risk patients, a more marked therapeutic effort must be made in order to improve survival

Objetivo: El objetivo del estudio fue identificar los factores pronósticos, las estrategias de manejo y los resultados de los cánceres cervicales localmente avanzados tratados en nuestro hospital. Material y métodos: Estudio retrospectivo de 156 pacientes con cánceres cervicales localmente avanzados (FIGO IB2-IVA). A todas las pacientes se les realizó estadiaje de los ganglios linfáticos paraaórticos mediante Tomografía Axial Computarizada. 93 pacientes con ganglios linfáticos paraaórticos sin signos de malignidad en las pruebas de imagen fueron sometidas a estadiaje quirúrgico preterapéutico hasta el nivel de la vena renal izquierda. Todas las pacientes fueron tratadas con quimio-radioterapia. Resultados: El estudio incluyo un total de 156 pacientes. La edad media fue de 54,04 años (rango 28-97 años). El carcinoma de células escamosas fue el tipo histológico más frecuente (82,1%). La mayoría de las paciente tenían un estadio FIGO IIB (43,6%). El estudio anatomopatológico reveló enfermedad metastásica en ganglios paraórticos en un 19,3% de la pacientes. El estado de los ganglios para-aórticos fue el único factor que se asoció de manera independiente con el incremento del riesgo de mortalidad [OR 33 (IC 95% 8-135,89; p<0,0001]. Conclusiones: Las pacientes con un estadio tumoral avanzado en el momento del diagnóstico y aquellas con ganglios paraórticos patológicos tienen mayor riesgo de desarrollar metástasis a distancia y mayores tasas de mortalidad causadas por la enfermedad. En este grupo de pacientes de alto riesgo se debe realizar un esfuerzo terapéutico superior con el fin de mejorar la supervivencia de esta enfermedad

Prog. obstet. ginecol. (Ed. impr.) ; 62(1): 43-46, ene.-feb. 2019. ilus
Artigo em Espanhol | LILACS-Express | ID: ibc-ET1-3589


La enfermedad de Paget pigmentada de la mama es una variante clinicopatológica infrecuente de la enfermedad de Paget, la cual debe incluirse en el diagnóstico diferencial de las lesiones pigmentadas del pezón. Se presenta el caso de una mujer de 49 años que consulta al presentar una mácula pigmentada en el pezón derecho de 9 meses de evolución; y cuyo estudio histológico e inmunohistoquímico permitió diagnosticar una Enfermedad de Paget que se acompaña de una hiperplasia melanocitaria atípica, diferenciándola de un melanoma maligno

Pigmented mammary Paget disease is an uncommon clinicopathological variant of Paget's disease, which should be included in the differential diagnosis of pigmented lesions on the nipple. We present the case of a 49-year-old woman with a 9-month-old pigmented lesión on her right nipple. The histological and immunohistochemical study allowed the diagnosis of a Paget's disease with intense atypical melanocytic hyperplasia, differentiating it from a malignant melanoma

J Clin Immunol ; 38(4): 513-526, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29882021


The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.

Deficiência de GATA2/complicações , Influenza Humana/diagnóstico , Influenza Humana/etiologia , Biomarcadores , Citocinas/sangue , Análise Mutacional de DNA , Evolução Fatal , Feminino , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Fator de Transcrição GATA2/genética , Humanos , Imunofenotipagem , Vírus da Influenza A , Influenza Humana/virologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Linhagem
Cancer Cell ; 33(6): 1078-1093.e12, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29894693


Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.

Glicosídeo Hidrolases/genética , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mutações Sintéticas Letais , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Recombinação Homóloga/efeitos dos fármacos , Recombinação Homóloga/genética , Humanos , Camundongos da Linhagem 129 , Camundongos Knockout , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli ADP Ribosilação/efeitos dos fármacos
J Cell Biol ; 212(3): 281-8, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26811421


Topoisomerase IIß-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOPBP1's role in HR, with potential clinical implications for cancer treatment.

Proteínas de Transporte/metabolismo , Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Recombinação Homóloga , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Rad51 Recombinase/metabolismo , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Células HeLa , Humanos , Proteínas Nucleares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Rad51 Recombinase/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção
J Med Genet ; 47(9): 635-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20798129


Genetic defects in the IL-12-IL-23/IFN-gamma circuit confer Mendelian susceptibility to mycobacteria and salmonella. The IL-12/IFN-gamma axis is essential for anti-tumoral immunity in mice. Cancer susceptibility has not been recognised in these patients so far. We report three relatives with IL-12R beta 1 deficiency. At the age of 25 years old, one patient presented with oesophageal squamous cell carcinoma (OSCC). The patient had no previous risk factors for OSCC. He died at the age of 29 years. OSCC is exceedingly rare in individuals under 30 years and frequently relates to alcohol intake and smoking. Disorders of the IL-12-IL-23/IFN-gamma axis may predispose to cancer.

Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Receptores de Interleucina-12/deficiência , Adolescente , Adulto , Carcinoma de Células Escamosas/patologia , Criança , Neoplasias Esofágicas/patologia , Evolução Fatal , Feminino , Humanos , Masculino , Receptores de Interleucina-12/metabolismo , Adulto Jovem
Rev. esp. patol ; 39(4): 243-245, oct.-dic. 2006. ilus
Artigo em Espanhol | IBECS | ID: ibc-054346


Introducción: El nefroma mesoblástico congénito (NMC) (hamartoma leiomiomatoso o mesenquimal) es una neoplasia renal congénita. Se diagnostica en los seis primeros meses de vida. Su comportamiento clínico es benigno y el tratamiento es quirúrgico. Paciente y métodos: Describimos el caso de un paciente de una semana de edad que presenta una masa renal. En la ecografía es sólida y sustituye al riñón. El TAC muestra una lesión con márgenes mal delimitados y la estructura heterogénea. Macroscópicamente en la pieza quirúrgica se identificaba una masa intrarrenal bien delimitada, sólida, homogénea, blanquecina y con aspecto fasciculado. Microscópicamente se observa una neoformación compuesta por una población monótona de células fusiformes dispuestas en haces entrelazados. La lesión carece de cápsula y en la interfase con el parénquima renal normal hay células tumorales que rodean a los túbulos y a los glomérulos. Conclusiones: La edad en el momento del diagnóstico y la correcta extirpación del riñón son los dos factores pronósticos más relevantes

Introduction: Congenital mesoblastic nephroma (CMN) (leiomomatous or mesenchymal hamartoma) is a benign congenital renal neoplasm. This tumor is usually diagnosed along the first six months of life and surgery is current treatment. Patient and methods: A one week of life patient with a renal mass is reported. Ultrasonographically, the mass appearance was solid and replaces the kidney. Computerized tomography (CT) showed a lesion with irregular margins and heterogeneous structure. Grossly, a well delimited intrarenal mass, white, solid, homogeneus and fasciculated was identified. Microscopically, the tumor was composed by a monotonous population of fusiform cells showing an interlacing fasciculated pattern. The mass lacks capsule and the interphase with normal renal parenchyma showed spindle cells surrounding renal tubuli and glomerula. Conclusions: Best prognostic factors are the adequate extirpation and age at the diagnosis

Masculino , Recém-Nascido , Humanos , Nefroma Mesoblástico/congênito , Hamartoma/congênito , Neoplasias Renais/congênito , Nefroma Mesoblástico/diagnóstico , Nefroma Mesoblástico/patologia , Nefroma Mesoblástico/cirurgia , Hamartoma/diagnóstico , Hamartoma/patologia , Hamartoma/cirurgia , Tomografia Computadorizada por Raios X , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia