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1.
Adv Clin Exp Med ; 29(2): 197-202, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32154678

RESUMO

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) is a complication of organ transplantation and a life-threatening condition. Children who underwent organ transplantation are at risk of developing lymphoproliferative disorders and, among them, non-Hodgkin lymphoma (NHL) is the most serious. OBJECTIVES: The objective of this study was to describe the clinical course of NHL after liver and kidney transplantation. MATERIAL AND METHODS: Retrospective analysis of medical records of children who underwent liver/kidney transplantation and developed NHL. RESULTS: Nine children were identified, all girls, 6 after liver and 3 after kidney transplantations. Age at transplantation ranged from 1 year to 13 years (median: 4 years), while age at lymphoma diagnosis from 4 to 17 years (median: 12 years). Time from transplantation to lymphoma diagnosis ranged from 7 months to 12 years (median: 9 years). All but 1 patient developed mature B-cell lymphoma, 4 children - diffuse large B-cell lymphoma (DLBCL), 2 children - Burkitt's lymphoma, 1 child - mature B-cell leukemia, 1 child - Burkitt-like lymphoma, while 1 patient was diagnosed with T-cell lymphoblastic lymphoma. High levels of Epstein-Barr virus (EBV) DNA were found in blood of 3 patients, and EBV in tissue samples was detected in 4 patients. Six patients presented with stage III and 2 with stage IV disease. Two patients had graft involvement. Three children received chemotherapy according to R-CHOP, 3 LMB protocol (2 with addition of rituximab), while 1 received CHOP and 5 courses of COP. T-cell lymphoma patient was treated with Euro-LB protocol. Six out of 8 treated patients are alive with a median follow-up of 6 years. Two children died from disease progression during treatment and 1 from cerebral herniation before starting therapy. All patients experienced at least 1 toxic episode of grade 3 and 4 according to Common Toxicity Criteria Adverse Event (CTCAE). Complications of chemotherapy were manageable and there were no transplanted organ failures. CONCLUSIONS: Our study provides further data on the treatment and outcome of monomorphic PTLD and indicates that it is feasible to treat solid organ recipients with multiagent chemotherapy.

2.
Diagn Pathol ; 14(1): 103, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31493794

RESUMO

BACKGROUND: The most frequent histological types of rhabdomyosarcoma (RMS) in children are embryonal (ERMS) and alveolar (ARMS) tumours. The majority of ARMS are characterized by the presence of PAX3/7-FOXO1 gene fusion and have a worse prognosis than fusion gene-negative ARMS. However, identification of PAX3/7-FOXO1 fusion status is challenging when using formalin-fixed, paraffin-embedded (FFPE) material. Microarray analyses revealed that high expression of several genes is associated with PAX3/7-FOXO1 fusion status. Therefore, we investigated if immunohistochemical approach may detect surrogate marker genes as indicators of fusion gene-positive RMS. METHODS: Forty five RMS patients were included in the analysis and immunohistochemistry was applied to FFPE tissues collected at diagnosis. Protein expression of OLIG2, a novel marker in RMS, was investigated using antibody EP112 (Cell Marque). In addition already known two markers were also analyzed: TFAP2B using rabbit anti-TFAP2ß antibody (Santa Cruz Biotechnology) and ALK using anti-ALK antibody clone D5F3 #3633 (Cell Signalling). Fluorescence in situ hybridization (FISH) was performed on FFPE sections with FOXO1/PAX3 and/or FOXO1/PAX7 probes (Dual Colour Single Fusion Probe, Zytovision). RESULTS: Our analysis revealed that all three immunohistochemical markers are associated with the presence of PAX3/7-FOXO1 fusion: TFAP2B (p < 0.00001), OLIG2 (p = 0.0001) and ALK (p = 0.0007). Four ARMS had negative PAX3/7-FOXO1 status and none of them displayed positive reaction with the analysed markers. Positive reaction with OLIG2 (6 tumours) was always associated with the presence of PAX3/7-FOXO1 rearrangement. Two additional OLIG2 positive cases showed inconclusive FISH results, but were positive for TFAP2B and ALK, what suggests that these tumours expressed fusion positive signature. CONCLUSION: Our results indicate that TFAP2B, ALK and a novel marker OLIG2 may serve as surrogate markers for PAX3/7-FOXO1 status what is especially beneficial in cases where poor quality tumour tissue is not suitable for reliable genetic analyses or shows inconclusive result.

3.
J Clin Immunol ; 35(6): 538-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26271390

RESUMO

PURPOSE: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. METHODS: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. RESULTS: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies. CONCLUSIONS: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Quebra de Nijmegen/diagnóstico , Fatores de Tempo , Adolescente , Adulto , Criança , Pré-Escolar , Instabilidade Cromossômica , Feminino , Humanos , Síndromes de Imunodeficiência , Lactente , Linfoma não Hodgkin , Masculino , Microcefalia , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/terapia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
4.
Blood ; 115(23): 4770-7, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20378756

RESUMO

The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS patients.


Assuntos
Diferenciação Celular/imunologia , Imunoglobulinas/imunologia , Síndrome de Quebra de Nijmegen/imunologia , Células Precursoras de Linfócitos B/imunologia , Hipermutação Somática de Imunoglobulina/imunologia , Adolescente , Adulto , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Criança , Pré-Escolar , Quebras de DNA de Cadeia Dupla , Feminino , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Lactente , Masculino , Complexos Multiproteicos/genética , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/metabolismo , Síndrome de Quebra de Nijmegen/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Recombinação Genética/genética , Recombinação Genética/imunologia , Hipermutação Somática de Imunoglobulina/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
5.
Clin Immunol ; 135(3): 440-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20167538

RESUMO

Selected viruses and immune parameters were monitored in 57 patients with Nijmegen breakage syndrome as a proposed tool for early detection of changes preceding development of malignancy. The following parameters were analysed: (1) viral infections; (2) monoclonal proteins; and (3) B-cell and T-cell receptor gene rearrangements in peripheral blood lymphocytes. Viral infections were detected in 68.4% of patients with a predominance of EBV (63.2%), followed by HBV (19.2%) and HCV (8.8%). Monoclonal gammopathy detected in 38.6% of cases correlated with the presence of EBV DNA (p=0.002) and HCV RNA (p=0.04). Clonal Ig and/or TCR gene rearrangements occurred in 73.9% of patients. The presence of at least one of the studied parameters preceded the development of malignancy in 22 patients. Systematic PCR analysis for viral infections and Ig/TCR gene rearrangements, supplemented by detection of monoclonal proteins, is advantageous in monitoring NBS patients before severe complications of the disease, including cancer, appear.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Hematológicas/etiologia , Síndrome de Quebra de Nijmegen/imunologia , Síndrome de Quebra de Nijmegen/virologia , Viroses/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Neoplasias Hematológicas/epidemiologia , Humanos , Lactente , Masculino , Síndrome de Quebra de Nijmegen/sangue , Paraproteinemias , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos T/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Viroses/complicações , Adulto Jovem
6.
J Pediatr Hematol Oncol ; 32(1): e28-30, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20051774

RESUMO

SUMMARY: Ataxia-telangiectasia is an autosomal recessive disorder caused by mutation in the ATM gene. Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasiae, cancer susceptibility, and variable humoral and cellular immunodeficiency. We report a patient who, because of the pattern of her immunodeficiency, was primarily diagnosed as an autosomal recessive hyper-IgM syndrome. Only a mild cerebellar ataxia was present at the age of 7 years then she developed a Wilms tumor (nephroblastoma). Conventional radiotherapy for the malignancy led to fatal consequences. Postmortem studies confirmed diagnosis of ataxia-telangiectasia.


Assuntos
Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM/etiologia , Radioterapia/mortalidade , Tumor de Wilms/radioterapia , Ataxia Cerebelar , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Tumor de Wilms/etiologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-19782616

RESUMO

OBJECTIVE: The objective of this study was to assess the oral cavity status of patients with Nijmegen breakage syndrome (NBS), an inherited genetic disorder that belongs to the group of chromosome instability syndromes and is characterized by microcephaly, a distinct facial appearance, growth retardation, radiation sensitivity, and immunodeficiency. STUDY DESIGN: Oral examination was conducted and immunological status assessed in 21 NBS patients (1.7-20.7 years old) and 21 healthy controls (5-21 years old). The differences between the frequency and severity of clinical manifestations and their correlation with immune parameters were analyzed by Student t test, the chi-square test, and Spearman's rank order correlation. RESULTS: Lesions of the oral mucosa and gingivitis were diagnosed more frequently in NBS patients than in controls. The mean Gingival Index was significantly higher in NBS subjects (P = 0.00043). Candidiasis was detected in 6 patients (28.6%) and in none of the healthy controls. Immune deficiency (humoral and/or cellular) was detected in 20 of 21 (95.2%) NBS patients. There was a significant association between severity of gingival inflammation and reduced number of B- and/or CD3+/CD4+ T cells combined with IgA+IgG4 deficiency. CONCLUSION: Our study showed that oral manifestations diagnosed in NBS patients were associated with combined deficiencies of the humoral and cellular arms of the immune system. We postulate that periodical examination of the oral cavity is essential for early medical intervention.


Assuntos
Candidíase Bucal/etiologia , Gengivite/etiologia , Síndrome de Quebra de Nijmegen/complicações , Adolescente , Estudos de Casos e Controles , Queilite/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Lactente , Contagem de Linfócitos , Masculino , Estomatite Aftosa/etiologia , Adulto Jovem
8.
Pediatr Blood Cancer ; 52(2): 186-90, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18937313

RESUMO

BACKGROUND: Due to small number of patients with Nijmegen Breakage Syndrome (NBS) and Non-Hodgkin lymphoma (NHL) experience in their treatment is limited. PROCEDURE: Since 1996, 17 patients with a median age of 9.5 years who had NBS, were treated for NHL. NHL type, stage, chemotherapy, dose modifications, chemotherapy delays, response to chemotherapy, toxicity, outcome and correlation of drug reduction with response to treatment and outcome were analyzed. RESULTS: Nine patients had TNHL, eight BNHL. TNHL patients received BFM and BNHL LMB type protocols. Doses of cytostatics were reduced in the first chemotherapy courses. Further modifications depended on severity of complications. None of the patients complied with timing of chemotherapy. Complete remissions after induction were achieved in 8 of 9 TNHL and 3 out 8 of BNHL patients. All patients experienced grade 4 toxicities. Two patients died from complications. Six of 17 patients are alive. All received more than 80% of recommended doses of chemotherapy. No differences in the type, number of responses or grade 3 and 4 toxicities between patients receiving less or more than 80% of drug doses were observed. Treatment related deaths concerned patients who received less than 80% of drug doses. CONCLUSIONS: Patients with NBS develop both T and B cell lymphomas. Treatment outcome is poor and might be improved by administering over 80% of drug doses. Although toxicity often depends upon drug doses, our patients experienced equal grade 3 and 4 toxicities whether they received more or less than 80% of the chemotherapeutic agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Síndrome de Quebra de Nijmegen/complicações , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfoma não Hodgkin/etiologia , Masculino , Síndrome de Quebra de Nijmegen/tratamento farmacológico , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Med Wieku Rozwoj ; 10(3 Pt 1): 819-29, 2006.
Artigo em Polonês | MEDLINE | ID: mdl-17317913

RESUMO

UNLABELLED: Non-rhabdomyosarcoma soft tissue sarcomas (NR STS) are a rare group of neoplasms of mesenchymal origin. The incidence of these tumours in children is low and due to it's heterogeneity and different response to chemotherapy and radiotherapy, unified treatment methods have not yet been established. THE AIM of our study was to analyze methods and treatment results of patients with NR STS treated in our centre. MATERIALS AND METHODS: Between 1996 and 2004, 64 patients with NR-STS, aged 2.5-21.5 yrs, were treated in our institution. Treatment protocol included primary tumour resection or biopsy, induction (neoadjuvant) chemotherapy, local treatment: surgery and/or radiotherapy and adjuvant chemotherapy. Results of treatment were analyzed in relation to stage, tumour diameter, extent of surgery and response to chemotherapy. RESULTS: Out of 64 patients, 48 are alive (75%), with a median observation time 4 yrs 3 m. Sixteen patients died: 1 of treatment complications, the rest from basic disease. Four years overall (OS) and event free survival (EFS) are 75% and 64% respectively. Early stage, tumour size less than 5 cm in diameter, radical surgery, complete and very good response to induction chemotherapy had a significant influence on survival. CONCLUSIONS: Our results indicate that besides stage and tumour size, radical surgery played key role in the treatment of NRMSSTS and that radical resections were possible to perform after induction chemotherapy in 33% of patients with primarily unresectable tumours. High number of patients with stage IV disease at diagnosis, occurrence of distant relapses and good response to chemotherapy indicate the necessity for the use of chemotherapy in patients with NR STS.


Assuntos
Sarcoma/epidemiologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/epidemiologia , Neoplasias de Tecidos Moles/terapia , Adolescente , Adulto , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Polônia/epidemiologia , Radioterapia Adjuvante , Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/radioterapia , Neoplasias de Tecidos Moles/cirurgia , Resultado do Tratamento
10.
Int J Cancer ; 118(5): 1269-74, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16152606

RESUMO

Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence.


Assuntos
Proteínas de Ciclo Celular/genética , Heterozigoto , Linfoma/genética , Mutação/genética , Proteínas Nucleares/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Linfoma/epidemiologia , Masculino , Polônia/epidemiologia
11.
Acta Neurobiol Exp (Wars) ; 64(4): 503-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15586667

RESUMO

The results of brain MRI are presented in 22 patients with documented Nijmegen breakage syndrome (NBS), aged from 1 and 9/12 to 20 years. T1-, PD or FLAIR and T2-weighted SE/TSE images in three planes were obtained. Twenty-one patients showed microcephaly. Decreased size of frontal lobes and narrow frontal horns of the lateral ventricles was observed in all cases. In 6 patients agenesis of the posterior part of the corpus callosum was found as well as colpocephaly and temporal horn dilatation. In 2 patients callosal hypoplasia was accompanied by other anomalies: abnormal cerebrospinal fluid spaces. Sinusitis was present in all patients as a result of primary immunodeficiency. As in ataxia teleangiectasia and other breakage syndromes, NBS patients show inherited malignancy susceptibility and hypersensitivity to X and gamma radiation. Because of that computed tomography is contraindicated in these patients and MRI should be the method of choice in diagnostic imaging.


Assuntos
Encéfalo/patologia , Quebra Cromossômica , Malformações do Sistema Nervoso/patologia , Adolescente , Adulto , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Angiografia por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Tomografia Computadorizada por Raios X
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