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The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.
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Background: Ewing sarcoma (EwS) is a rare and highly malignant bone tumor primarily affecting children, adolescents, and young adults. The pelvis, trunk, and lower extremities are the most common sites, while EwS of the sacrum as a primary site is very rare, and only few studies focusing on this location are published. Due to the anatomical condition, local treatment is challenging in sacral malignancies. We analyzed factors that might influence the outcome of patients suffering from sacral EwS. Methods: We retrospectively analyzed data of the GPOH EURO-E.W.I.N.G 99 trial and the EWING 2008 trial, with a cohort of 124 patients with localized or metastatic sacral EwS. The study endpoints were overall survival (OS) and event-free survival (EFS). OS and EFS were calculated using the Kaplan-Meier method, and univariate comparisons were estimated using the log-rank test. Hazard ratios (HRs) with respective 95% confidence intervals (CIs) were estimated in a multivariable Cox regression model. Results: The presence of metastases (3y-EFS: 0.33 vs. 0.68; P < 0.001; HR = 3.4, 95% CI 1.7 to 6.6; 3y-OS: 0.48 vs. 0.85; P < 0.001; HR = 4.23, 95% CI 1.8 to 9.7), large tumor volume (≥200 ml) (3y-EFS: 0.36 vs. 0.69; P=0.02; HR = 2.1, 95% CI 1.1 to 4.0; 3y-OS: 0.42 vs. 0.73; P=0.04; HR = 2.1, 95% CI 1.03 to 4.5), and age ≥18 years (3y-EFS: 0.41 vs. 0.60; P=0.02; HR = 2.6, 95% CI 1.3 to 5.2; 3y-OS: 0.294 vs. 0.59; P=0.01; HR = 2.92, 95% CI 1.29 to 6.6) were revealed as adverse prognostic factors. Conclusion: Young age seems to positively influence patients` survival, especially in patients with primary metastatic disease. In this context, our results support other studies, stating that older age has a negative impact on survival. Tumor volume, metastases, and the type of local therapy modality have an impact on the outcome of sacral EwS. Level of evidence: Level 2. This trial is registered with NCT00020566 and NCT00987636.
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The genetic diversity of the human leukocyte antigen (HLA) system was shaped by evolutionary constraints exerted by environmental factors. Analyzing HLA diversity may allow understanding of the underlying pathways and offer useful tools in transplant setting. The aim of this study was to investigate the HLA haplotype diversity in patients with sickle cell disease (SCD, N = 282) or ß-thalassemia (ß-Thal, N = 60), who received hematopoietic cell transplantation (HCT) reported to Eurocord and the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). We identified 405 different HLA-A-B-DRB1 haplotypes in SCD and 108 in ß-Thal patients. Using data from African and European populations of the "1000 Genomes Project" for comparison with SCD and ß-Thal, respectively, we found that the haplotypes HLA-A*30-B*14-DRB1*15 (OR 7.87, 95% CI: 1.66-37.3, p b = 0.035), HLA-A*23-B*08 (OR 6.59, 95% CI: 1.8-24.13, p b = 0.023), and HLA-B*14-DRB1*15 (OR 10.74, 95% CI: 3.66-31.57, p b = 0.000) were associated with SCD, and the partial haplotypes HLA-A*30-B*13 and HLA-A*68-B*53 were associated with ß-Thal (OR 4.810, 95% CI: 1.55-14.91, p b = 0.033, and OR 17.52, 95% CI: 2.81-184.95, p b = 0.011). Our results confirm the extreme HLA genetic diversity in SCD patients likely due to their African ancestry. This diversity seems less accentuated in patients with ß-Thal. Our findings emphasize the need to expand inclusion of donors of African descent in HCT donor registries and cord blood banks.
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PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.
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Neoplasias Ósseas , Sarcoma de Ewing , Humanos , Masculino , Feminino , Sarcoma de Ewing/patologia , Ácido Zoledrônico/uso terapêutico , Estudos Prospectivos , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/patologiaRESUMO
BACKGROUND: Local treatment is a crucial element in the standard of care for Ewing sarcoma (EWS). While systemic treatment is improved in randomised clinical trials, local treatment modalities are discussed controversially. We analysed the association between local therapy and event-free survival (EFS), overall survival (OS), and local recurrence (LR) in prospectively collected data of patients with localised EWS. PATIENTS AND METHODS: We analysed data from the international Ewing 2008 study registered between 2009 and 2019 in 117 centres. After induction chemotherapy, patients received surgery, radiotherapy, or a combination thereof. We performed Cox regression, conducted propensity score-weighted sensitivity analysis, and performed subgroup analyses. Hazard ratios (HRs) and 95% confidence intervals are reported. RESULTS: We included 863 patients with localised EWS (surgery alone: 331, combination therapy: 358, definitive radiotherapy: 174). In patients treated with combination therapy compared to surgery alone, EFS HR was 0.84 (0.57-1.24; p = 0.38), OS HR was 0.84 (0.57-1.23; p = 0.41), and LR HR was 0.58 (0.26-1.31; p = 0.19). Hazards of any event were increased in patients treated with definitive radiotherapy compared to surgery only, HR 1.53 (1.02-2.31; p = 0.04). Patients with poor responses to chemotherapy benefitted from combination therapy over definitive surgery with an EFS HR 0.49 (0.27-0.89; p = 0.02). Patients with pelvic tumours benefitted from combination therapy over surgery only regarding LR, HR 0.12 (0.02-0.72; p = 0.02). CONCLUSION: Patients with poor responses to chemotherapy benefitted from radiotherapy added to surgery. In the whole group, radiotherapy alone as opposed to surgery alone increased the hazards of any event.
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Radioterapia (Especialidade) , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/terapia , Intervalo Livre de Progressão , Terapia Combinada , Quimioterapia de InduçãoRESUMO
Introduction: Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10. Case presentation: We diagnosed a 9-year-old girl of normal appearance and severe refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation of VHL gene (c.414A>G), also present in three members of her family. At age 13, a pelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life. Discussion: This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine.
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BACKGROUND: Paediatric palliative care (PPC) aims to improve children's quality of life, but this outcome is rarely measured in clinical care. PPC is provided in Belgium through six transmural paediatric liaison teams (PLTs) ensuring continuity of care for children with life-limiting or life-threatening conditions (LLC/LTC). This study aims to measure the quality of life (QoL) of children with LLC/LTC followed-up by PLTs and the QoL of their parents. METHODS: During interviews, an original socio demographic questionnaire, the Children palliative outcome scale-version 2 (CPOS-2), the Fragebogen für Kinder und Jugendliche zur Erfassung der gesundheitsbezogenen Lebensqualität (KINDL) and the Quality of life in life-threatening Illness-Family caregiver (QOLLTI-F) were filled in by PLT members. Statistics were used to investigate significant differences between scores. Results were discussed and interpreted with six PLTs. RESULTS: 73 children aged 1-18 were included in the study. Especially for items focusing on emotional items, children reported their QoL as higher than their parents did. The QoL scores were not significantly associated with the child's condition's severity. CONCLUSIONS: This study provides, for the first time, an overview of the QoL of children and parents followed-up by PLTs in Belgium.
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Purpose: Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS. Methods and Materials: The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response. Results: S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P = .42) and in the RT group 52.9%, 62.5%, and 70.3% (P = .63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P = .96; histologic response, P = .07; tumor volume, P = .50; dose, P = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P = .15; age, P = .08; sex, P = .40). Conclusions: In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.
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The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.
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Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Humanos , Criança , Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Doença de Erdheim-Chester/genética , Mutação , ÉxonsRESUMO
Splenectomy improves the clinical parameters of patients with hereditary spherocytosis, but its potential benefit to red blood cell (RBC) functionality and the mechanism behind this benefit remain largely overlooked. Here, we compared 7 nonsplenectomized and 13 splenectomized patients with mutations in the ß-spectrin or the ankyrin gene. We showed that hematological parameters, spherocyte abundance, osmotic fragility, intracellular calcium, and extracellular vesicle release were largely but not completely restored by splenectomy, whereas cryohemolysis was not. Affected RBCs exhibited decreases in ß-spectrin and/or ankyrin contents and slight alterations in spectrin membrane distribution, depending on the mutation. These modifications were found in both splenectomized and nonsplenectomized patients and poorly correlated with RBC functionality alteration, suggesting additional impairments. Accordingly, we found an increased abundance of septins, small guanosine triphosphate-binding cytoskeletal proteins. Septins-2, -7, and -8 but not -11 were less abundant upon splenectomy and correlated with the disease severity. Septin-2 membrane association was confirmed by immunolabeling. Except for cryohemolysis, all parameters of RBC morphology and functionality correlated with septin abundance. The increased septin content might result from RBC maturation defects, as evidenced by (1) the decreased protein 4.2 and Rh-associated glycoprotein content in all patient RBCs, (2) increased endoplasmic reticulum remnants and endocytosis proteins in nonsplenectomized patients, and (3) increased lysosomal and mitochondrial remnants in splenectomized patients. Our study paves the way for a better understanding of the involvement of septins in RBC membrane biophysical properties. In addition, the lack of restoration of septin-independent cryohemolysis by splenectomy may call into question its recommendation in specific cases.
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Espectrina , Esferocitose Hereditária , Humanos , Espectrina/genética , Espectrina/metabolismo , Septinas/genética , Septinas/metabolismo , Esplenectomia , Anquirinas/genética , Anquirinas/metabolismo , Esferocitose Hereditária/cirurgia , Esferocitose Hereditária/genética , Eritrócitos/metabolismoRESUMO
Background: Extrarenal rhabdoid tumours (ERT) are highly aggressive tumours that are poorly responsive to standard cytotoxic chemotherapy and are associated with a grim prognosis. Primary ERT of the liver are most commonly observed in early childhood and exceptionally rare later in life. Case presentation: We report the case of a 16-year-old male patient, presenting with flu-like symptoms after his second COVIDvaccination. During the work-up, a large solid liver lesion was incidentally discovered upon abdominal ultrasound examination. Pathological examination rendered the diagnosis of primary ERT of the liver, characterized by the loss of expression of INI-1 protein, encoded by the SMARCB1 gene. We summarized and discuss the existing literature by reviewing 53 pediatric and 6 adult cases, including the histological features treatment and outcomes of primary hepatic ERT. Conclusion: Primary ERT of the liver are usually not associated with specific signs or symptoms, making the diagnosis very challenging. As ERT are associated with a high metastatic rate, delayed diagnoses lead to increased mortality, as complete resection is not possible in advanced-stage cases. Therefore, early diagnoses, enabling complete resection of the tumour are crucial to improve patient outcomes. Of interest, primary ERT of the liver, is associated with biallelic loss of the SMARCB1 (SWI/ SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) gene, a potential target for cancer therapeutics. This is, to our knowledge, the first case of a hepatic rhabdoid tumour treated with liver transplantation.
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Neoplasias Hepáticas , Tumor Rabdoide , Sarcoma , Adolescente , Humanos , Masculino , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Tumor Rabdoide/terapiaRESUMO
Background: To assess whether expectant observation of infants ≤ 90 days old with small suprarenal masses (sSRMs) could avoid unnecessary surgery without impacting outcome. Methods: Infants ≤ 90 days with a ≤ 5 cm mass, without midline extension or lymph node or distant spread were registered (ClinicalTrials.org:NCT01728155). Once staging was completed, they were followed with ultrasound, MRI and urinary catecholamines. Surgical resection was only planned if there was a ≥40% mass volume increase or for a mass persisting after 48 weeks of the planned observation. Results: Over a 5-year period, 128 infants were registered. No infant had detectable MYCN amplification in the peripheral blood. Surgery was performed in 39 (30.5%) patients, in 18 during and in 21 after the planned 48-week observation, and 74% were confirmed to be neuroblastomas. Non-life-threatening surgical complications occurred in two cases. The 3-year overall survival and event-free survival were 100% and 87.1%, respectively. The 16 events observed were volume increase (N = 11) and progression to neuroblastoma stage MS (N = 5). Patients with solid masses or MIBG-positive masses had lower EFS. Conclusions: Expectant observation for infants with sSRMs with clinical follow-up and timely imaging (including MRI scan) is safe and effective, allowing surgery to be avoided in the majority of them.
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High-throughput sequencing (HTS) of the immunoglobulin heavy chain (IgH) locus is a recent very efficient technique to monitor minimal residual disease of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It also reveals the sequences of clonal rearrangements, therefore, the multiclonal structure, of BCP-ALL. In this study, we performed IgH HTS on the diagnostic bone marrow of 105 children treated between 2004 and 2008 in Belgium for BCP-ALL in the European Organization for Research and Treatment of Cancer (EORTC)-58951 clinical trial. Patients were included irrespectively of their outcome. We described the patterns of clonal complexity at diagnosis and investigated its association with patients' characteristics. Two indicators of clonal complexity were used, namely, the number of foster clones, described as clones with similar D-N2-J rearrangements but other V-rearrangement and N1-joining, and the maximum across all foster clones of the number of evolved clones from one foster clone. The maximum number of evolved clones was significantly higher in patients with t(12;21)/ETV6:RUNX1. A lower number of foster clones was associated with a higher risk group after prephase and t(12;21)/ETV6:RUNX1 genetic type. This study observes that clonal complexity as accessed by IgH HTS is linked to prognostic factors in childhood BCP-ALL, suggesting that it may be a useful diagnostic tool for BCP-ALL status and prognosis.
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INTRODUCTION: The ETV6::NTRK3 fusion is the most common gene alteration in infantile fibrosarcoma, a soft tissue tumor affecting patients under two years of age. Less frequently, these tumors harbor fusions of genes encoding other kinases, such as BRAF, which activates MEK in the mitogen-activated protein kinase pathway. The identification and characterization of these oncogenes are crucial to facilitate diagnosis, validate new treatments, and better understand the pathophysiology of these neoplasms. METHODS: Herein, we analyzed an ETV6::NTRK3-negative infantile fibrosarcoma from a 5-day-old patient by RNA-sequencing to identify new fusion transcripts. Functional exploration of the fusion of interest was performed by in vitro assays to study its activity, oncogenicity, and sensitivity to the MEK inhibitor trametinib. RESULTS: We identified a novel fusion involving the PHIP and BRAF genes. The corresponding fusion protein constitutively activated the mitogen-activated protein kinase pathway, resulting in fibroblast transformation. Treatment of transfected cells with trametinib effectively inhibited signaling by PHIP::BRAF. CONCLUSION: PHIP::BRAF is a novel fusion oncogene that can be targeted by trametinib in infantile fibrosarcoma.
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Fibrossarcoma , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Musculares , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas B-raf , Fibrossarcoma/genética , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Neoplasias Musculares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
PURPOSE: Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS: Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS: Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION: In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.
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Sarcoma de Ewing , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bussulfano/análogos & derivados , Criança , Quimioterapia de Consolidação , Ciclofosfamida , Intervalo Livre de Doença , Doxorrubicina , Etoposídeo , Humanos , Masculino , Melfalan , Estudos Prospectivos , Sarcoma de Ewing/tratamento farmacológico , VincristinaRESUMO
BACKGROUND: Secondary forms of diabetes are often understudied and underdiagnosed in children and adolescents with cancer. The objectives of our cohort study were to study the incidence and risk factors for hyperglycaemia in leukaemia and lymphoma patients. METHODS: We retrospectively collected 15 years of data from paediatric patients treated for acute lymphoblastic leukaemia (ALL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL) immediately at cancer diagnosis. We studied risk factors for hyperglycaemia in univariate and multivariate analyses. RESULTS: Our study cohort included 267 patients corresponding to 179 patients with ALL, 48 with NHL and 40 with HL. Eighteen per cent of ALL patients (32/179) and 17% of NHL patients (8/48) developed hyperglycaemia, with more than 61% developing hyperglycaemia within the first month of treatment. No hyperglycaemia was observed in HL patients. Multivariate analysis showed the following hyperglycaemia risk factors for ALL patients: overweight or obesity (OR 3.793) and pubertal onset (OR 4.269) at cancer diagnosis, steroid-resistant disease (OR 3.445) and hematopoietic stem cell transplant (HSCT) (OR 4.754). CONCLUSION: In our cohort, 18% of patients with ALL or NHL developed early-onset hyperglycaemia after chemotherapy/radiotherapy. Patients with ALL with increased hyperglycaemia risk can be readily identified by measuring BMI and puberty stage at cancer diagnosis. Also, glucose monitoring should be reinforced when patients show steroid-resistant disease and/or require HSCT.
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Neoplasias Hematológicas/terapia , Hiperglicemia/epidemiologia , Medição de Risco/métodos , Adolescente , Bélgica/epidemiologia , Glicemia/metabolismo , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Feminino , Neoplasias Hematológicas/complicações , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Incidência , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing's sarcoma resection surgery. Chronic infection by Clostridium hathewayi, Proteus mirabilis and Finegoldia magna was worsened by methicillin-susceptible Staphylococcus aureus exhibiting an inducible Macrolides-Lincosamides-Streptogramin B resistance phenotype (iMLSB). After failure of conventional conservative treatment, combination of in situ anti-S. aureus PT with surgical debridement and intravenous antibiotic therapy led to marked clinical and microbiological improvement, yet failed to prevent a recurrence of infection on the midterm. This eventually led to surgical graft replacement. Multiple factors can explain this midterm failure, among which incomplete coverage of the polymicrobial infection by PT. Indeed, no phage therapy against C. hathewayi, P. mirabilis or F. magna could be administered. Phage-antibiotic interactions were investigated using OmniLog® technology. Our results suggest that phage-antibiotic interactions should not be considered "unconditionally synergistic", and should be assessed on a case-by-case basis. Specific pharmacodynamics of phages and antibiotics might explain these differences. More than two years after final graft replacement, the patient remains cured of her sarcoma and no further infections occurred.
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Aloenxertos/microbiologia , Antibacterianos/farmacologia , Osso e Ossos/microbiologia , Coinfecção/terapia , Terapia por Fagos/métodos , Infecções Estafilocócicas/terapia , Fagos de Staphylococcus/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Aloenxertos/efeitos dos fármacos , Biofilmes , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Criança , Interações Medicamentosas , Feminino , Humanos , Sarcoma de Ewing/tratamento farmacológico , Infecções Estafilocócicas/diagnósticoRESUMO
Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of all paediatric cancer deaths. High-risk neuroblastoma is a particularly challenging-to-treat form of disease that requires multimodality treatment, consisting of chemotherapy, surgery, high-dose chemotherapy with autologous haematopoietic stem cell rescue, radiotherapy and differentiation therapy. However, despite intense multimodal treatment regimens, the prognosis for this patient population remains poor. In recent years, immunotherapy with anti-disialoganglioside 2 (anti-GD2) antibodies was found to improve survival rates for patients with high-risk neuroblastoma. Based on studies led by the SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) group, the anti-GD2 antibody dinutuximab beta was approved for use in high-risk neuroblastoma by the European Medicines Agency and has been implemented into the standard of care in many countries across Europe. However, immunotherapy with dinutuximab beta is associated with a number of adverse events that may be challenging for clinicians, such as pain, fever, hypersensitivity reactions and capillary leak syndrome. While these adverse events are considered manageable, there are currently no formal guidelines to support clinicians with their management. The aim of this article is to discuss the management of the most common adverse events encountered in clinical practice and to provide practical guidance to assist clinicians in minimising toxicity associated with dinutuximab beta.
Assuntos
Anticorpos Monoclonais , Neuroblastoma , Anticorpos Monoclonais/efeitos adversos , Humanos , Fatores Imunológicos , Imunoterapia/efeitos adversos , Neuroblastoma/tratamento farmacológicoRESUMO
BACKGROUND: Living donor liver transplantation is a treatment option for unresectable hepatic tumors in children. METHODS: We enrolled 45 living donor transplantations performed between 1993 and 2018 for liver malignacies, which included hepatoblastoma (n = 33), hepatocellular carcinoma (n = 10), hepatic angiosarcoma (n = 1), and rhabdomyosarcoma (n = 1). RESULTS: No mortality or major morbidities were encountered in any donor, and the complication rate was 9%. In the hepatoblastoma group, 5-year overall and event-free survival rate in recipients was 87.4% and 75.8%, respectively, and mortality was significantly higher in patients after rescue transplantation (p = .001). Inferior vena cava replacement in these recipients appeared to be associated with reduced mortality (p = .034), but this was not confirmed when rescue patients were excluded (p = .629). In hepatocellular carcinoma group, both 5-year overall and event-free survival rates were 75.4% each, and invasion of hepatic veins was significantly associated with increased risk of recurrence and death (p = .028). The patient with rhabdomyosarcoma died from EBV-induced lymphoma 2 months after transplantation. The patient with angiosarcoma was in complete remission at the last follow-up. Overall, 5-year graft survival rate was 81.3%, and one patient underwent re-transplantation due to chronic rejection. CONCLUSIONS: Pediatric oncological liver transplantation has become a key player in the management of malignancies with cancer cure in 84% of patients in this series. Living donor liver transplantation for pediatric recipients with unresectable tumors might be a beneficial surgical option, which is technically safe for donors and recipients, thus, allowing timely planning according to chemotherapy protocols.