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1.
Oncologist ; 24(9): e921-e929, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30850560

RESUMO

BACKGROUND: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. PATIENTS AND METHODS: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed. RESULTS: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. CONCLUSION: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. IMPLICATIONS FOR PRACTICE: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

3.
Leuk Lymphoma ; : 1-9, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29966458

RESUMO

Anthracyclines are integral components of antileukemic treatment. Apart from cardiotoxicity, myelosuppression and infectious complications have been described for doxorubicin (DOX) and daunorubicin (DNR) as predominant side effects, but little is known about their differential toxicities. To address the question whether DNR is associated with a lower rate of infectious complications compared with DOX, 307 children with newly diagnosed acute lymphoblastic leukemia, enrolled in trial CoALL 08-09, were randomized to receive either DOX 30 mg/m2 (n = 153) or DNR 36 mg/m2 (n = 154) in delayed intensification. Hematologic toxicities and stomatitis were less frequent in the DNR group resulting in a significantly lower rate of infections in the DNR arm (27% vs. 59%, p < .0001). Survival was equal in both arms (95% SE 2%) (p = .55), with an insignificant difference in the relapse rate (RR 0.12 (SE = 0.03) in the DOX arm vs. 0.16 (SE = 0.04) in the DNR arm; p = .37; Hazard ratio 1.3; 95% confidence interval 0.7-2.6). In conclusion, DNR given in delayed intensification is associated with a lower incidence of infectious complications without loss of efficacy.

4.
World J Pediatr ; 14(4): 322-329, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30054848

RESUMO

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor affecting infants and young children. Although benign, it can be associated with an aggressive locally growing tumor and/or a life-threatening Kasabach-Merritt phenomenon (KMP). To date, only reviews of limited cases have been performed. We, therefore, conducted a comprehensive literature search to collect relevant data and make recommendations for future treatment trials. METHODS: Review of the available literature between 1993 and 2017 revealed a total of 105 publications involving 215 patients of less than 21 years of age. To this, we added 12 from our department and 4 from the Cooperative Weichteilsarkomstudie database. RESULTS: We found that KMP was present in 79% of the infants, in 47% of the 1-5-year olds, in 43% of the 6-12-year olds, and in 10% of the 13-21-year-old patients. KMP was present in nearly all (94%) patients with retroperitoneal tumors and in all patients with extra-regional tumors. The median size of a KHE without KMP was 12 cm2 as compared to 49 cm2 when associated with a KMP. With complete (not further classifiable if R0 or R1) resection, all patients were cured. If inoperable, response regarding KMP/regression of tumor size was seen in 29/28% with steroid-, 47/39% with vincristine-, 44/43% with interferon alpha-, 65/61% with anti-platelet agents-, and in 97/100% with sirolimus-containing therapies. CONCLUSIONS: Patients with progressive KHE should undergo resection whenever it is considered a safe option. If inoperable, sirolimus should be the first choice for treating KMP and reducing tumor size.

5.
Clin Immunol ; 191: 52-58, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29567430

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inherited disorder leading to severe organ-specific autoimmunity. IPEX is caused by hemizygous mutations in FOXP3, which codes for a master transcription factor of regulatory T (TReg) cell development and function. We describe a four-year-old boy with typical but slightly delayed-onset of IPEX with autoimmune diabetes mellitus, enteropathy, hepatitis and skin disease. We found the unreported FOXP3 splice site mutation c.816+2T>A that leads to the loss of leucine-zipper coding exon 7. RNA-Seq revealed that FOXP3Δ7 leads to differential expression of FOXP3 regulated genes. After myeloablative conditioning the patient underwent allogeneic HSCT from a matched unrelated donor. HSCT led to the resolution of all IPEX symptoms including insulin requirement despite persisting autoantibody levels. After initial full donor engraftment nearly complete autologous reconstitution was documented, but donor-derived TReg cells persisted with a lineage-specific chimerism of >70% and the patient remained in clinical remission.

6.
Liver Int ; 38(7): 1280-1291, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29314711

RESUMO

BACKGROUND & AIMS: MicroRNAs are important genetic regulators of physiological and pathophysiological processes including cancer initiation and progression of hepatoblastoma, the most common liver tumour in childhood. We aimed to identify malignant and metastasis promoting effects of miR-492, a miRNA, previously reported to be overexpressed in metastatic hepatoblastoma. Furthermore, we intended to evaluate its diagnostic and prognostic potential. METHODS: Stable and transient overexpression of miR-492 in two liver tumour cell lines HepT1 and HUH7 was used to analyse features of metastatic tumour progression such as proliferation, anchorage-independent growth, migration and invasion. Via a mass spectrometry based proteomic screen, we investigated miRNA-492-dependent effects on proteome level and explored the underlying biology. One of the predicted target genes, CD44, was experimentally validated via luciferase assays. Diagnostic and prognostic properties of miR-492 were studied in hepatoblastoma tumour samples. RESULTS: We show that miR-492 significantly enhances cell proliferation, anchorage-independent growth, migration and invasion of hepatoblastoma cells. We also identified and validated CD44, a transmembrane adhesion receptor for hyaluronan, as direct and functional target of miR-492. This miRNA has a strong direct impact on two CD44 isoforms (standard and v10). High miR-492 expression correlates with high-risk or aggressive tumours and further bears potential for predicting reduced event-free survival. CONCLUSIONS: We identified miR-492 and its target CD44 as regulators of a number of biological features important for malignancy and metastasis. Furthermore, we demonstrated the diagnostic and prognostic potential of miR-492, a promising novel therapeutic target and biomarker for hepatoblastoma.

8.
J Allergy Clin Immunol ; 141(1): 322-328.e10, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28392333

RESUMO

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

10.
Ann Hematol ; 96(8): 1373-1377, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28573314

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the possibility of cure for sickle cell disease (SCD) patients. Unfortunately, the probability of finding an HLA-matched donor for SCD patients is low. HSCT from HLA-haploidentical donors using reduced intensity conditioning, unmanipulated bone marrow and post-transplantation cyclophosphamide (ptCy) has resulted in negligible toxicity but high rates of graft rejection. We hypothesized that combining ptCy with a myeloablative reduced toxicity conditioning including serotherapy to increase immune ablation would allow for better engraftment. In a pilot approach, we treated three patients with SCD (5, 8, and 20 years old) lacking a matched donor. All patients had severe disease-related complications despite standard treatment. They received unmanipulated bone marrow from parental HLA-haploidentical donors. Conditioning consisted of alemtuzumab 0.2 mg/kg/day on days -9 and -8, fludarabine 30 mg/m2/day on days -7 to -3, treosulfan 14 g/m2/day on days -7 to -5, thiotepa 2 × 5 mg/kg/day on day -4, and cyclophosphamide 14.5 mg/kg/day on days -3 and -2. GVHD prophylaxis was performed using cyclophosphamide 2 × 50 mg/kg on days +3 and +4 and mycophenolate mofetil, tacrolimus from day +5. After a follow-up of 11, 14, and 30 months, all three patients are alive and well, off immunosuppression, and without symptoms of SCD. One patient experienced mild skin GVHD grade I, none showed chronic GVHD. Asymptomatic CMV reactivation was seen in two patients. HLA-haploidentical HSCT can extend the donor pool for patients with SCD. Whether intensification of the conditioning regimen and intensive immunosuppression leads to improvement in engraftment rates while still allowing a favorable toxicity profile deserves further investigation.


Assuntos
Anemia Falciforme/terapia , Ciclofosfamida/uso terapêutico , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade , Humanos , Masculino , Agonistas Mieloablativos/uso terapêutico , Projetos Piloto , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Adulto Jovem
11.
J Hepatocell Carcinoma ; 4: 15-21, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28144610

RESUMO

Hepatocellular carcinoma (HCC) is a very rare entity in children, making it nearly impossible to orchestrate Phase II/III studies even as multinational cooperative trials. In contrast to adults, nearly 50% of the children have a response (α-fetoprotein decline and/or tumor shrinkage) to chemotherapeutic agents such as cisplatin and doxorubicin (PLADO), demonstrating that HCC in childhood can be chemotherapy sensitive. As a result, the main treatment options in pediatric HCC focus on systemic drug therapies and resection as the central therapy. In nonmetastatic patients with complete resection upfront, the 5-year event-free survival and overall survival has reached 80%-90%. In almost all reported studies, children received adjuvant chemotherapy (mostly PLADO), but it has never been proven that postoperative chemotherapy is superior to observation. No data are available for the effects of sorafenib. The 3-year survival is <20% in children with unresectable HCC independent of the chemotherapy given preoperatively. Currently, PLADO in combination with sorafenib is recommended with the goal of achieving operability status. Alternatively, data are promising for the combination of sorafenib with gemcitabine and oxaliplatin. For children with nonresectable and nonmetastastic liver tumors, it has been shown that the Milan criteria regarding liver transplantation are not applicable - individual decisions have to be made. Transarterial chemoembolization could be offered to patients with chemotherapy-resistant liver tumors for palliative care or potentially to achieve surgical resectability, and therefore cure. Information about the feasibility or effects of new agents or approaches as discussed in adult HCC patients is not available for childhood HCC. Research has to be done for characterizing the molecular and genomic mechanisms of pediatric HCC to support the development of novel therapeutic approaches and the implementation of personalized medicine.

12.
Pediatr Blood Cancer ; 64(8)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28111878

RESUMO

Recently, studies in adults with acute promyelocytic leukemia (APL) showed high cure rates in low-risk patients treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO), while toxicities were significantly reduced compared to the standard treatment with ATRA and chemotherapy. Here we report about first experience with 11 pediatric patients with low-risk APL treated with ATRA and ATO. All patients stayed in molecular remission. All suffered from hyperleukocytosis. Two patients experienced reversible severe side effects. One suffered from osteonecroses at both femurs, seizures, as well as posterior reversible encephalopathy syndrome, the other patient had an abducens paresis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/administração & dosagem , Tretinoína/administração & dosagem , Adolescente , Trióxido de Arsênio , Arsenicais/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Óxidos/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Tretinoína/efeitos adversos
14.
Lancet Oncol ; 18(1): 122-131, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27884679

RESUMO

BACKGROUND: Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. METHODS: The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. RESULTS: Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. INTERPRETATION: We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). FUNDING: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.


Assuntos
Hepatoblastoma/secundário , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias/normas , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Comportamento Cooperativo , Bases de Dados Factuais , Feminino , Seguimentos , Hepatoblastoma/terapia , Humanos , Lactente , Recém-Nascido , Agências Internacionais , Japão , Neoplasias Hepáticas/terapia , Metástase Linfática , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , alfa-Fetoproteínas/metabolismo
15.
Cancer Med ; 5(8): 1765-75, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27228363

RESUMO

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (±0.10) and 45% (±0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials.


Assuntos
Neoplasias Encefálicas/terapia , Tumor Rabdoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Europa (Continente)/epidemiologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Sistema de Registros , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Falha de Tratamento , Resultado do Tratamento
16.
Eur J Pediatr ; 175(6): 793-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26898704

RESUMO

UNLABELLED: Red blood cell transfusion can improve but also might temporarily reduce the microcirculation. The buccal microcirculation was visualized and total vessel density (TVD) determined with sidestream dark field imaging in 19 pediatric anemic (Hb 7.2 g/dL, 95 % CI 6.5-7.9) oncology or hematology patients receiving red blood cell transfusions (Tx) and in 18 age-matched healthy non-anemic controls. After transfusion, Hb (8.0 g/dL, 95 % CI 7.3-8.6) and TVD increased (14.7 ± 1.7 versus 16.6 ± 2.0 mm/mm(2)) significantly with a concomitant decrease in RBC velocity in medium-sized vessels (pre-Tx 711 ± 199 versus post-Tx 627 ± 163 µm/s). Compared to the controls, pre-Tx TVD (17.5 ± 1.3 mm/mm(2)) was lower and RBC velocity (476 ± 77 µm/s) was significantly higher. After transfusion, TVD and RBC velocity remained significantly lower and higher, respectively. In a subgroup, analysis of the transfused children with infection of TVD at baseline was lower with a larger increase after transfusion compared to anemic children without infection (ΔTVD 3.4 ± 2.6 versus ΔTVD 1.3 ± 1.5 mm/mm(2)). CONCLUSION: With the rise of hemoglobin after transfusion, significant improvements of tissue perfusion were demonstrated but differences to non-anemic controls persisted. In particular, the microcirculation of anemic oncology patients with infection improved after transfusion. WHAT IS KNOWN: • Transfusions can improve but also temporarily reduce the microcirculation. • In neonates, transfusion significantly increases total vessel density. What is New: • Pretransfusion, the microcirculation of the anemic children differed significantly from the controls. • After transfusion, the microcirculation improved but still differed from the controls. • These changes were most profound in anemic patients with concurrent infection, therefore transfusion threshholds might need to be higher.


Assuntos
Anemia/sangue , Transfusão de Eritrócitos , Microcirculação , Mucosa Bucal/irrigação sanguínea , Adolescente , Anemia/diagnóstico por imagem , Anemia/terapia , Estudos de Casos e Controles , Criança , Índices de Eritrócitos , Feminino , Humanos , Masculino , Estudos Prospectivos
17.
J Exp Clin Cancer Res ; 35: 9, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26762252

RESUMO

BACKGROUND: In this study we explored the role of microRNAs (miRNAs) as mediators of leukemogenic effects of the fusion gene MLL-AF9, which results from a frequent chromosomal translocation in infant and monoblastic acute myeloid leukemia (AML). METHODS: We performed a specific and efficient knockdown of endogenous MLL-AF9 in the human monoblastic AML cell line THP1. RESULTS: The knockdown associated miRNA expression profile revealed 21 MLL-AF9 dependently expressed miRNAs. Gene ontology analyses of target genes suggested an impact of these miRNAs on downstream gene regulation via targeting of transcriptional modulators as well as involvement in many functions important for leukemia maintenance as e.g. myeloid differentiation, cell cycle and stem cell maintenance. Furthermore, we identified one of the most intensely repressed miRNAs, miR-511, to raise CCL2 expression (a chemokine ligand important for immunosurveillance), directly target cyclin D1, inhibit cell cycle progression, increase cellular migration and promote monoblastic differentiation. With these effects, miR-511 may have a therapeutic potential as a pro-differentiation agent as well as in leukemia vaccination approaches. CONCLUSIONS: Our study provides new insights into the understanding of miRNAs as functional mediators of the leukemogenic fusion gene MLL-AF9 and opens new opportunities to further investigate specific therapeutic options for AML via the miRNA level.


Assuntos
Perfilação da Expressão Gênica/métodos , Leucemia Monocítica Aguda/genética , MicroRNAs/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Ciclo Celular , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Quimiocina CCL2/genética , Ciclina D1/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Leucemia Monocítica Aguda/metabolismo
18.
Glob Pediatr Health ; 3: 2333794X16681934, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28229095

RESUMO

Introduction: Acute ischemic stroke (AIS) is a rare event in infancy. Besides vasculopathy, thrombophilia, or cardiac disorders, cancer and chemotherapy are known predisposing factors for AIS. Leukemia can be associated with different abnormal coagulation parameters, but severe bleeding or thrombosis occurs rarely. Clinical Course: We report the case of a 2-year-old boy who was presented to our emergency ward after a prolonged seizure with right sided postictal hemiparesis. Cranial computed tomography scan revealed a large infarction and edema due to thrombosis of the left carotid artery, the middle cerebral artery, and the anterior cerebral artery. Laboratory workup showed 196 g/L leukocytes with 75% myeloid blast cells. Immediate exchange transfusion, hydration, and chemotherapy with cytarabine were started. During the hospital course intracranial pressure increased and the patient developed a unilateral dilated pupil unresponsive to light. Cranial computed tomography scan revealed a new infarction in the right middle cerebral artery territory. Refractory increased intracranial pressure and brain stem herniation developed, and the child died 3 days after admission to hospital. Conclusion: Seizures with postictal hemiparesis due to cerebral infarction can be a rare manifestation of acute myeloid leukemia. Leukocytosis and cancer-induced coagulopathy are main reasons for thrombosis and/or hemorrhage. High leukocyte counts need immediate interventions with hydration, careful chemotherapy, and perhaps exchange transfusion or leukapharesis. In the presence of thrombosis, anticoagulation must be discussed despite the risk of bleeding due to hyperfibrinolysis and low platelet counts. Mortality may be reduced by awareness of this rare presentation of leukemia and prompt institution of leucoreductive treatment.

19.
J Crohns Colitis ; 10(1): 112-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26464403

RESUMO

BACKGROUND AND AIMS: X-linked chronic granulomatous disease [X-CGD] due to hemizygous mutations in CYBB is characterised by invasive bacterial and fungal infections and granulomatous inflammation. Inflammatory bowel disease [IBD] is an additional or isolated manifestation. Allogeneic haematopoietic stem cell transplantation [alloHSCT] is the standard curative treatment. X-CGD carriers are usually healthy but those with non-random X-chromosome inactivation [XCI] may develop infectious or autoinflammatory manifestations. METHODS AND RESULTS: We report on two female patients with severe treatment-refractory Crohn-like IBD manifesting at age 23 and 8 years, respectively. NADPH-oxidase activity testing and molecular genetics proved X-CGD carrier status with non-random XCI. As in CGD, histopathology from colonic biopsies disclosed pigment-laden macrophages and reduced CD68(+) macrophages. Following submyelo-ablative conditioning, the younger patient was treated with alloHSCT at age 20 years. She came into remission within 3 months after transplantation and shows complete mucosal healing after 16 months off all medications. CONCLUSIONS: We suggest that children and young adults with refractory IBD should mandatorily be tested for CGD. AlloHSCT should be considered as curative therapy in severely diseased female carriers of X-CGD with non-random XCI.


Assuntos
Doença de Crohn/genética , Doença de Crohn/terapia , Predisposição Genética para Doença , Doença Granulomatosa Crônica/genética , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Adulto , Aloenxertos , Biópsia por Agulha , Doença de Crohn/patologia , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Heterozigoto , Humanos , Imuno-Histoquímica , Mutação de Sentido Incorreto , NADPH Oxidase 2 , Medição de Risco , Amostragem , Índice de Gravidade de Doença , Resultado do Tratamento , Inativação do Cromossomo X/genética , Adulto Jovem
20.
Cancer Lett ; 370(2): 275-8, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26577641

RESUMO

DICER1, a RNAse endonuclease involved in the processing of siRNA and microRNA, is known to play a pivotal role in the post-transcriptional regulation of gene expression. Germ line mutations in the DICER1 gene increase the risk for different types of tumors. At present, DICER1 syndrome is an established, though not well defined, member of the group of genetic tumor predisposition syndromes. Here, we report a DICER1 syndrome family with a medical history of different rare tumors mostly occurring at a young age. The tumor spectrum in this family included both DICER1 syndrome-typical forms, such as pleuropulmonary blastoma, multinodular goiter, and cystic nephroma, and not previously reported manifestations, such as pilomatrixoma, and juvenile basal cell carcinoma. The latter tumor types are usually considered to be indicators of familial adenomatous polyposis and basal cell nevus syndrome.


Assuntos
RNA Helicases DEAD-box/genética , Predisposição Genética para Doença , Mutação , Neoplasias/genética , Ribonuclease III/genética , Adolescente , Adulto , Feminino , Genes APC , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome
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