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1.
Cancer ; 129(5): 780-789, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36571557

RESUMO

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Transtornos Linfoproliferativos , Transtornos Mieloproliferativos , Transplante de Órgãos , Criança , Humanos , Masculino , Feminino , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Estudos Prospectivos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Linfoma não Hodgkin/complicações , Linfoma Difuso de Grandes Células B/patologia , Transtornos Mieloproliferativos/complicações , Estudos Retrospectivos , Transplante de Órgãos/efeitos adversos
2.
Br J Haematol ; 200(3): 297-305, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36454546

RESUMO

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.


Assuntos
Linfoma de Burkitt , Transtornos Linfoproliferativos , Transplante de Órgãos , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Linfoma de Burkitt/terapia , Linfoma de Burkitt/tratamento farmacológico , Transplante de Órgãos/efeitos adversos , Ciclofosfamida/uso terapêutico , Rituximab/uso terapêutico , Prednisona/uso terapêutico , Transtornos Linfoproliferativos/etiologia , Resultado do Tratamento , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
4.
Proc Natl Acad Sci U S A ; 110(22): E2074-83, 2013 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-23674691

RESUMO

A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM "sheddase" function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor-driven ADAM-10 activity and MET shedding are jointly dysregulated with disease.


Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Movimento Celular/fisiologia , Endometriose/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Membrana/metabolismo , Proteólise , Proteína ADAM10 , Proteína ADAM17 , Líquido Ascítico/metabolismo , Linhagem Celular , Biologia Computacional/métodos , Retroalimentação Fisiológica/fisiologia , Feminino , Humanos , Microscopia Eletrônica de Transmissão , Modelos Biológicos , Proteômica , Proteínas Proto-Oncogênicas c-met/metabolismo
5.
BMC Med Genet ; 12: 69, 2011 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-21595954

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1α. We hypothesized that the rs8192678 PGC-1α single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP. METHODS: Genomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model. RESULTS: The rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027). CONCLUSIONS: These data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1α in PD and longevity.


Assuntos
Estudos de Associação Genética , Proteínas de Choque Térmico/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Longevidade/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Polimorfismo de Nucleotídeo Único/genética , Risco
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