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1.
Adv Clin Exp Med ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430069

RESUMO

BACKGROUND: Unmanipulated haploidentical stem cell transplantation (haploSCT) with post-transplant cyclophosphamide is an option for patients with advanced hematologic malignancies. It offers a platform both for non-major histocompatibility complex-restricted alloimmunity due to killer-like immunoglobulin receptor (KIR)-mediated mechanisms of natural killer lymphocyte regulation and for classical T-cell mediated antileukemic effects. OBJECTIVES: The devastating long-term sequelae after total body irradiation (TBI) in children are encouraging omission of irradiation techniques in pediatric stem cell transplantations (SCT). MATERIAL AND METHODS: Five children, 4 with acute leukemia and 1 with hemophagocytic lymphohistiocytosis, aged from 1 to 10 years, underwent haploSCT with post-transplantation cyclophosphamide. In all children, the conditioning regimen consisted of chemotherapy without TBI. The graft material was bone marrow (BM) in 4 cases and peripheral blood stem cells in 1 case. Three out of 5 leukemic patients showed better KIR haplotype associated with augmented alloreactivity. RESULTS: Engraftment with complete donor chimerism was achieved in 4 patients, and 1 recipient died before leukocyte recovery. Three patients developed skin acute graft-versus-host-disease (aGvHD), 1 gut aGvHD and 1 liver aGvHD. In 2 recipients, chronic graft-versus-host-disease (cGvHD) was observed (1 limited and 1 extensive). The 4 engrafted patients were alive and in complete remission 3, 9, 32, and 36 months after transplantation. A T-cell count of 200 cells/uL was reached 90 days after haploSCT in all patients. CONCLUSIONS: HaploSCT with TBI-free protocols can be a viable option for heavily pretreated patients with advanced malignancies.

2.
Adv Clin Exp Med ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31430073

RESUMO

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Identifying its risk factors would enable the proper prophylaxis and management, which may significantly improve the general outcome of children treated with HSCT. OBJECTIVES: The aim of this single-center, retrospective cohort study was to assess the potential risk factors for grades II-IV of aGvHD in children after the 1st allo-HSCT from an unrelated donor (UD), performed as a result of an underlying malignant disease. MATERIAL AND METHODS: From among patients who received HSCT in our center in the years 2004-2015, 237 were included in the study cohort. All the patients received standard aGvHD prophylaxis consisting of cyclosporine (CsA) and a short course of methotrexate (MTX). Various clinical and epidemiological features, the transplant proceedings, graft composition, conditioning regimens, as well as the duration and coherence of aGvHD prophylaxis were analyzed as potential risk factors for aGvHD. RESULTS: The incidence of II-IV aGvHD in the study cohort was 58.6%. The median time of the diagnosis of aGvHD was 18 days post-HSCT. In the multivariate analysis, risk factors significantly associated with grades II-IV of aGvHD were: myeloablative conditioning regimen containing total body irradiation (TBI-MAC) (RR (relative risk): 1.69; p = 0.03), premature termination of CsA administration due to its toxicity (RR: 1.99; p = 0.0003) and HSCT performed before the year 2009 (RR: 1.97; p = 0.0001). Donor and recipient age, donor-recipient sex mismatch, stem cell source, risk of disease, and amount of infused CD34+ cells seem to be insignificant as risk factors for aGvHD. The overall survival (OS) of patients with aGvHD was noticeably worse that in those who were aGvHD-free: 60.8% vs 74.1% (p = 0.08). CONCLUSIONS: The conditioning regimen and the proper aGvHD prophylaxis, including continuous CsA administration, have a major impact on aGvHD occurrence. According to our results, the termination of CsA therapy should be carefully considered, and avoided if possible.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31205222

RESUMO

Eltrombopag (ELT) is a thrombopoietin receptor activator that has shown efficacy in chronic immune thrombocytopenia. We report the outcome of ELT therapy in 4 children who were treated for rare hematological disorders, including Pearson syndrome, DiGeorge syndrome, posttransplant allogeneic poor graft function (PGF), and Wiskott-Aldrich syndrome. The ELT tolerance in the analyzed group was good, with the exception of the child with Pearson syndrome, who experienced an exacerbation of cataracts and had to discontinue treatment. Thromboembolic events were observed in one child, who continued ELT therapy despite achieving normalized platelet counts. Independence from PLT transfusions was observed at the 4-week timepoint of therapy in patients with DiGeorge syndrome and PGF who responded to ELT. Discontinuation of therapy was successful in one child, who sustained the normal CBC values afterward. In 2 patients, an increase in neutrophil counts was observed during ELT therapy without additional intervention, and a positive correlation between neutrophil and platelet values during ELT therapy was observed in the child with PGF. ELT is effective in rare pediatric disorders, but response patterns are determined by the underlying disease. ELT shows promising results in patients, but constitutional hematopoiesis defects reduce the chances of a response.

4.
J Clin Apher ; 34(5): 563-570, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31141215

RESUMO

BACKGROUND: Apheresis in children with low body weight is technically limited by their tolerance of the extracorporeal blood volume. STUDY DESIGN AND METHODS: This paper presents a single-center experience with 23 procedures in 12 children with weights between 5.2 and 9.5 kg using the Spectra Optia mononuclear cell (MNC) protocol with blood priming. RESULTS: The average procedure duration was 158 minutes, and the median processed blood volume was 316 mL/kg. The white blood cell (WBC), platelet (PLT), and hemoglobin (HGB) values showed a downward trend with increased volume of processed blood. The post-apheresis HGB concentration was increased in all procedures due to initial priming with packed red blood cells (PRBCs), but this effect disappeared at a level of ~400 mL of processed blood/kg. The median volume of the cellular product was 36 mL, the WBC count was 153 K/µL, the hematocrit (HCT) was 1.5%, the PLT count was 602 K/µL, the WBC collection efficacy (CE2) was 13.2%, and the PLT CE2 was 9.5%. The median CD34+ CE2 was 28%, and interpolation of the CD34+ CE2 yielded a Y-intercept value of 32%. Higher pre-collection CD34+ counts resulted in higher CD34+ yields. No correlation was found between the pre-collection CD34+ results and CD34+ CE2. CONCLUSION: The analyzed data demonstrated the feasibility and safety of apheresis in very low-weight children. The laboratory abnormalities were asymptomatic and citrate toxicity was mild. Visual control of clogging with manual adjustment of the citrate infusion rate is important to reduce exposure to citrate.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31085306

RESUMO

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

6.
Neoplasia ; 21(3): 294-310, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30763910

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles. To extend miRNome characteristics in T-ALL (to 82 T-ALL cases), we combined our small RNA-seq results with data available in Gene Expression Omnibus. We report on miRNAs most abundantly expressed in pediatric T-ALL and miRNAs differentially expressed in T-ALL versus normal mature T-lymphocytes and thymocytes, representing candidate oncogenic and tumor suppressor miRNAs. Using eight target prediction algorithms and pathway enrichment analysis, we identified differentially expressed miRNAs and their predicted targets implicated in processes (defined in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of potential importance in pathogenesis of T-ALL, including interleukin-6-mediated signaling, mTOR signaling, and regulation of apoptosis. We finally focused on hsa-mir-106a-363 cluster and functionally validated direct interactions of hsa-miR-20b-5p and hsa-miR-363-3p with 3' untranslated regions of their predicted targets (PTEN, SOS1, LATS2), overrepresented in regulation of apoptosis. hsa-mir-106a-363 is a paralogue of prototypic oncogenic hsa-mir-17-92 cluster with yet unestablished role in the pathogenesis of T-ALL. Our study provides a firm basis and data resource for functional analyses on the role of miRNA-mRNA interactions in T-ALL.


Assuntos
Regulação Leucêmica da Expressão Gênica , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Interferência de RNA , RNA Mensageiro/genética , Transcriptoma , Apoptose/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Genes Reporter , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico
7.
Biol Blood Marrow Transplant ; 24(11): 2245-2249, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30454873

RESUMO

Ataxia-telangiectasia (A-T) syndrome is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ataxia-telangiectasia mutated gene manifested by progressive neurodegeneration, telangiectasias of sclera and skin, immune deficiency with sinopulmonary infections, and increased incidence of lymphoid malignancies and solid tumors. Three children with A-T underwent allogeneic stem cell transplantation (SCT) using protocols for Fanconi anemia. All 3 patients were engrafted with a mixed donor-recipient chimerism, but the full donor engraftment was observed in the T lymphocyte compartment. Immunologic recovery resulted in T cell production and lack of symptomatic infections. Regular intravenous immunoglobulin supplementation was needed until IgG production recovered, which depended on pretransplant serotherapy. During the observation period patients did not require hospital admission, and none of the transplanted patients developed sinopulmonary infections. Neurologic functions in reported patients were impaired and slowly deteriorated after transplantation, but no immediate toxicities were observed. The following hallmark features of A-T were present after SCT: neurologic symptoms, growth failure, telangiectasia formation, or increased serum alpha fetoprotein. SCT can help control immune deficiency constituting 1 of the features of A-T, and elimination of autologous hematopoiesis reduces the risk of lymphoid malignancies. Resolving crucial problems with qualification for SCT depends on balancing the risk and benefits of transplant therapy.

8.
Oncotarget ; 9(32): 22741-22748, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29854312

RESUMO

Background: Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a graft-versus-tumor effect in pediatric sarcoma patients. Here, we describe general feasibility, toxicity and efficacy of DLI after allo-SCT. Results: 4 of 8 patients responded. ES#4 had stable disease (SD) for 9 months after DLI and RMS#4 partial response for 8 months with combined hyperthermia/chemotherapy. In ES#4, DLI led to SD for 6 months and reverted residual disease before allo-SCT into complete remission. After DLI, ES#4 and RMS#4 developed acute GvHD (°III-°IV), ES#4 also developed chronic GvHD. 5 patients including ES#4 lived longer than expected. Median survival after allo-SCT was 2.3 years, post-relapse survival (PRS) was 13 months. Off note, HLA-mismatched DLI were associated with a trend towards increased survival after allo-SCT and increased PRS compared to HLA-matched DLI (23 versus 3 months). Materials and Methods: We studied eight adolescents and young adults (AYAs) with advanced Ewing sarcoma (ES#1-4) and rhabdomyosarcoma (RMS#1-4) who received DLI. Escalating doses ranged from 2.5 × 104 to 1 × 108 CD3+ cells/kg body weight. AYAs were evaluated for response to DLI, graft-versus-host disease (GvHD) and survival. Conclusions: DLI after allo-SCT may control advanced pediatric sarcoma in AYAs with controllable toxicity.

9.
Adv Clin Exp Med ; 27(1): 91-98, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29521048

RESUMO

BACKGROUND: Chronic myeloid leukemia (CML) constitutes only 2-3% of all leukemias in pediatric patients. Philapelphia chromosome and BCR-ABL fusion are genetic hallmarks of CML, and their presence is crucial for targeted molecular therapy with tyrosine kinase inhibitors (TKIs), which replaced hematopoietic stem cell transplantation (HSCT) as a standard first-line therapy. The disease in pediatric population is rare, and despite molecular and clinical similarities to CML in adults, different approach is needed, due to the long lifetime expectancy and distinct developmental characteristics of affected children. OBJECTIVES: The objective of this study is to evaluate treatment with imatinib in Polish pediatric patients with CML. MATERIAL AND METHODS: We analyzed the results of treatment with imatinib in 57 pediatric patients (June 2006 - January 2016) from 14 Polish pediatric hematology and oncology centers. RESULTS: In the study group, 40 patients continued imatinib (median follow-up: 23.4 months), while in 17 the treatment was terminated (median follow-up: 15.1 months) due to therapy failure. In the latter group, 13 patients underwent HSCT, while 4 switched to second-generation TKIs. The 5-year overall survival rate (OS) in the study group was 96%, and the 5-year event-free survival (EFS) was 81%. CONCLUSIONS: Our results confirm that the introduction of TKI therapy has revolutionized the treatment of CML in the pediatric population by replacing the previous method of treatment with HSCT and allowing a high percentage of OS and EFS.

10.
Med Mycol ; 56(1): 121-124, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28340159

RESUMO

We studied the presence of triazole resistance of 121 Aspergillus fumigatus clinical isolates collected in two Polish cities, Warsaw and Wroclaw, to determine if resistance is emerging in our country. We identified five itraconazole resistant isolates (4.13%) carrying the TR34/L98H alteration in Cyp51A gene, four of which were cross-resistant to posaconazole and one to voriconazole. One isolate was intermediate susceptible to itraconazole and harbored no Cyp51A alterations. The study confirms the presence of azole resistant A. fumigatus strains in Poland at a level that is comparative to other European countries.


Assuntos
Antifúngicos/farmacologia , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/isolamento & purificação , Farmacorresistência Fúngica , Triazóis/farmacologia , Cidades , Sistema Enzimático do Citocromo P-450/genética , Proteínas Fúngicas/genética , Genótipo , Humanos , Mutação de Sentido Incorreto , Polônia
11.
Nat Commun ; 8(1): 2126, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259247

RESUMO

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.


Assuntos
Metilação de DNA , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Antineoplásicos/uso terapêutico , Biópsia , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Análise Mutacional de DNA , Epigenômica , Feminino , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/patologia , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Mutação , Síndrome de Noonan/patologia , Prognóstico , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-cbl , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Regulação para Cima
12.
Clin Cancer Res ; 23(15): 4224-4232, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28228384

RESUMO

Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrow-derived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224-32. ©2017 AACR.


Assuntos
Evolução Clonal/genética , Recidiva Local de Neoplasia/genética , Segunda Neoplasia Primária/genética , Neuroblastoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Pré-Escolar , Cromossomos Humanos Par 19/genética , Intervalo Livre de Doença , Feminino , Deleção de Genes , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Segunda Neoplasia Primária/patologia , Células Neoplásicas Circulantes/patologia , Neuroblastoma/patologia , Polimorfismo de Nucleotídeo Único/genética , Recidiva , Proteína Nuclear Ligada ao X/genética
13.
Adv Clin Exp Med ; 25(4): 611-5, 2016 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27629833

RESUMO

BACKGROUND: Chronic limb ischemia is a serious clinical problem. Patients who do not qualify for standard treatment may benefit from novel gene therapies. OBJECTIVES: This study evaluated angiogenesis following intramuscular injections of angiogenic plasmid Ang-1 in Fisher rats. MATERIAL AND METHODS: Twenty rats had plasmids injected intramuscularly in their hind limbs. The study group consisted of 10 animals which received the Ang-1 plasmid, while the control group consisted of 10 rats that received an empty plasmid. All the animals were euthanized after 12 weeks and tissue samples from the hind limb thigh muscles and internal organs were harvested for histological and immunohistochemical examinations. To assess the angiogenesis the number of vessels in the hind limb muscles visualized by the SMA and FVIII markers was counted for each animal in five separate microscopic fields. RESULTS: There were no pathological lesions or any signs of neoplastic angiogenesis in any of the 20 rats. The number of vessels visualized by the FVIII marker in the study group was two times higher than in the control group (median: 12, range: 7-25 vs. median: 6, range: 2-15; p < 0.0001). The median estimated that the number of vessels visualized by the SMA marker is 63% higher in the study group compared to the control group (median: 6.5, range: 1-12 vs. median: 4, range: 0-10; p = 0.0008). CONCLUSIONS: Intramuscular injections of Ang-1 plasmids induced angiogenesis in the rat hind limb muscles.


Assuntos
Angiopoietina-1/metabolismo , Neovascularização Fisiológica/fisiologia , Animais , Membro Posterior/irrigação sanguínea , Plasmídeos , Ratos , Ratos Endogâmicos F344
14.
Pediatr Neonatol ; 57(4): 295-301, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26934827

RESUMO

BACKGROUND: Advances in multidisciplinary care for pediatric cancer have resulted in significant improvement in cure rates over the last decades; however, these advances have not been uniform across all age groups. Cancer is an important cause of perinatal mortality, yet the full spectrum of malignant neoplasms in newborns is not well defined. METHODS: The authors have reviewed the clinical features and outcomes of 37 newborns with congenital malignant tumors treated at three referral centers in North, Central, and South Poland between 1980 and 2014. Event-free survival (EFS) and overall survival (OS) rates were estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. RESULTS: Twenty-two patients were diagnosed prenatally. The most common diagnoses were neuroblastoma (48.7%), followed by malignant germ-cell tumor (16.2%), and Wilms' tumor (8.1%). Neuroblastoma was the most common malignancy among full-term infants, and malignant sacrococcygeal teratoma was the most common malignancy in premature infants. Thirty patients (81%) are alive with a median follow-up of 4.8 years from diagnosis. Patients with Wilms' tumor and malignant germ-cell tumors had the best outcomes (5-year OS 100% for both), whereas the worst prognosis was observed for sarcoma patients (5-year OS 72.92%). Premature infants had better outcome than full-term infants (5-year OS 92.8% vs. 72.58%, respectively). CONCLUSION: Although rare, neonatal cancers can present with an aggressive clinical behavior, but they have a generally good outcome. Early diagnosis and management by expert multidisciplinary teams that integrate perinatal medicine experts with pediatric and surgical oncologists are critical. Centralized care with clear referral pathways that facilitate early initiation of specialized treatment should be prioritized.


Assuntos
Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/mortalidade , Doenças do Prematuro/patologia , Masculino , Polônia/epidemiologia , Encaminhamento e Consulta , Estudos Retrospectivos , Taxa de Sobrevida
15.
Int J Cancer ; 139(1): 153-63, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26910568

RESUMO

Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN-FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment.


Assuntos
Amplificação de Genes , Heterogeneidade Genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Adolescente , Aneuploidia , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/patologia , Polimorfismo de Nucleotídeo Único
16.
Blood ; 127(11): 1387-97; quiz 1518, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26702063

RESUMO

Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT.


Assuntos
Fator de Transcrição GATA2/deficiência , Síndromes Mielodisplásicas/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Ensaios Clínicos Fase III como Assunto , Análise Mutacional de DNA , Surdez/genética , Feminino , Fator de Transcrição GATA2/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Síndromes de Imunodeficiência/genética , Estimativa de Kaplan-Meier , Masculino , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia , Fenótipo , Prevalência , Prognóstico , Estudos Prospectivos , Viés de Seleção , Adulto Jovem
17.
Klin Oczna ; 117(2): 101-3, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26638547

RESUMO

We describe the case of a 16-month-old girl with neuroblastoma and chronic lymphocytopenia due to chemotherapy and treosulfan-containing megatherapy who developed cytomegalovirus retinitis and neuritis. Intravenous ganciclovir and anti-cytomegalovirus immunoglobulin were used with a transient benefit; however, retrobulbar gancyclovir resulted in a complete remission. This report emphasizes the need for close monitoring of viral infections in patients undergoing treosulfan-containing megatherapy, highlighting the immunosuppressive effects of this agent, and indicates the potential use of retrobulbar ganciclovir as the alternative method of drug delivery.


Assuntos
Antivirais/administração & dosagem , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Ganciclovir/administração & dosagem , Retinite/tratamento farmacológico , Retinite/etiologia , Antineoplásicos Alquilantes/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Bussulfano/efeitos adversos , Bussulfano/análogos & derivados , Feminino , Humanos , Lactente , Leucemia/complicações , Leucemia/terapia , Resultado do Tratamento
18.
Haematologica ; 100(1): 17-22, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25552679

RESUMO

Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.


Assuntos
Ensaios Clínicos como Assunto/normas , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/terapia , Recidiva Local de Neoplasia/prevenção & controle , Guias de Prática Clínica como Assunto/normas , Criança , Terapia Combinada , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Prognóstico , Taxa de Sobrevida
19.
Cytometry B Clin Cytom ; 84(3): 179-86, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23475399

RESUMO

BACKGROUND: Defects in early B lymphocyte maturation in bone marrow (BM) compose a characteristic feature of many primary immune deficiencies associated with agammaglobulinemia. To date, only limited data on the composition of the precursor B-cell compartment in BM is available. The aim of this study was to define normal age-related ranges of total B-cell content and distribution of precursor B-cell stages in BM for the future use in clinical diagnostics. METHODS: Four color flow cytometry was used to analyze the composition of the B-cell compartment in specimens from 59 hematologically healthy children, aged 14 days to 16 years, assigned to six age groups: neonates less than 1 month old, infants >1-12 months old, children >1-2 years old, >2-5 years old, >5-10 years old, and older than 10 years. RESULTS: Analysis of the composition of the B-cell compartment revealed significant age-related variation in the distribution of individual B-cell maturation stages, most seriously affecting children during first 2 years of life, with the shift from domination of the earliest stages, to gradually increasing content of mature B-cells. Significantly higher proportions of pro-B lymphocytes were observed in neonates than in any other age group. CONCLUSION: Physiological age-related variation in the precursor B-cell compartment composition affects most seriously very young children below the age of 2 years. Proper interpretation of immunophenotyping results performed in cases of suspected early B-cell differentiation defect requires application of adequate reference data.


Assuntos
Antígenos CD/análise , Células da Medula Óssea/citologia , Imunofenotipagem/normas , Células Precursoras de Linfócitos B/citologia , Adolescente , Fatores Etários , Antígenos CD/imunologia , Células da Medula Óssea/imunologia , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Lactente , Recém-Nascido , Masculino , Células Precursoras de Linfócitos B/imunologia
20.
Cancer Genet ; 205(5): 261-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22682626

RESUMO

Translocations of the MLL gene are common among neonates and infants with acute lymphoblastic and acute myeloid leukemias. We characterized a new three-way translocation involving MLL in an infant with acute myeloid leukemia who subsequently relapsed and underwent a hematopoietic stem cell transplant from an unrelated stem cell donor. The translocation was characterized using karyotyping and fluorescence in situ hybridization. In this patient, a complex rearrangement fused the distal part of 11q23 with 17q11.2, the distal part of 17q11.2 with 1q21, and the distal part of 1q21 with 11q23, resulting in a three-way translocation; t(1;11;17)(q21;q23;q11.2). The two reciprocal MLL fusion sites were cloned by long-distance inverse polymerase chain reaction, which led to the identification of MLL-MLLT11 and the reciprocal MYO18A-MLL fusion alleles. Both fusion genes are in-frame and can be translated into functional fusion proteins. Although the MLL-MLLT11 fusion gene has been described in the literature, the reciprocal MYO18A fusion partner is a novel candidate gene in the growing list of reciprocal MLL fusions.


Assuntos
Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Miosinas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética , Sequência de Bases , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Cariótipo , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide/química , Miosinas/química , Proteínas de Neoplasias/química , Proteínas Proto-Oncogênicas/química , Alinhamento de Sequência
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