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Sarcomas characterized by BCOR gene alterations, are a distinct clinico-pathological group of high-grade tumors, that represent 5% of small round cell tumors without EWSR or FUS fusion. Diverse genetic alterations characterize this group, including BCOR-CCNB3 gene fusion being the most common alteration and less frequently internal tandem duplications (ITDs). We present a compelling case of a 3-year-old girl diagnosed with a high-grade nasoethmoidal sarcoma exhibiting BCOR-ITD. The diagnostic process illustrates the histological and immunophenotypic spectrum, requiring an extensive immunohistochemical panel and diverse molecular tests for accurate classification. Additionally, this case highlights the challenges in detecting BCOR-ITDs using different NGS panels, advocating for alternative molecular approaches. Our patient after 10 months since diagnosis is alive with progressive disease. This emphasizes the urgency for ongoing research to refine diagnostic methods and develop effective therapeutic strategies for these rare and aggressive tumors.
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INTRODUCTION: High-dose methotrexate (HDMTX) is administered for the treatment of some cancers. HDMTX is usually safe but may crystallize in renal tubules causing acute kidney injury (AKI). Consequently, MTX elimination is delayed, resulting in a severe and life-threatening condition. No studies have been published about the impact of MTX toxicity in Spain. This study aims to estimate the incidence and management of MTX delayed elimination and toxicity. METHODS: A two-round Delphi study was performed to reach consensus between 10 medical experts on haemato-oncology and paediatric oncology with experience in the management of HDMTX treated patients from leading Spanish hospitals. An online questionnaire was developed based on national and international guidelines and previous evidence regarding HDMTX-related toxicity. Consensus was established at 80% agreement. Median and interquartile ranges were calculated, and incidence data were extrapolated to the Spanish general population. RESULTS: Out of 1.475 patients estimated to receive HDMTX treatment annually in Spain, 27.5% present MTX delayed elimination and 11.6% develop HDMTX-induced AKI (35.4% with severe systemic toxicities (>grade 3) and 18.8% develop chronic renal disease). Mortality is estimated in 4.2%. Immuno-enzymatic assay is used in most of the hospitals (90%) for MTX serum level monitoring. All experts use increased supportive care and high leucovorin as first-line treatment. Available treatments in experts' hospitals in case toxicity persists are haemodialysis (90% of hospitals), glucarpidase (60%) and hemofiltration (50%). Most prevalent non-renal systemic toxicities are haematologic and mucositis (21-40% of patients). Patients with HDMTX-induced AKI require from intensive care (5% of patients), more than 3 sessions and 4 days of dialysis, and about 8.5 days of hospitalization (non-ICU patients) and 12 days in case of patients requiring ICU. CONCLUSIONS: These results are the first evidence regarding HDMTX-induced AKI in Spain. Incidence and mortality results are in line with previous studies. Clinical management is based on preventive measures and the treatment depend on the availability in the hospital. The need for effective, safe and rapid treatment for the reduction of MTX toxic levels and the improvement of monitoring methods were noted by experts as urgent needs. Further observational studies to validate these results would be needed.
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Injúria Renal Aguda , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Criança , Humanos , Metotrexato/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Técnica Delphi , Incidência , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Neoplasias/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológicoRESUMO
Polybrominated diphenyl ethers (PBDE) are ubiquitous environmental pollutants. Exposure to these chemicals has been associated with developmental neurotoxicity, endocrine dysfunctions, reproductive disorders, and hepatotoxicity. The widespread use of PBDE as flame retardants has culminated in daily exposure of humans and wildlife to these contaminants and resulted in their banned use. Thus assessment of the potential effects of each PBDE congener on living organisms has become cause for concern. The aim of this study was to (1) examine the effects of decabromodiphenyl ether (BDE)-209 on different functions of HepG2 cells and (2) investigate whether this congener is involved in mitochondrial toxicity. The use of multiple methods was employed to (i) study the influence of BDE-209 on mitochondrial permeability transition (MPT) process in mitochondria isolated from rat liver and (ii) determine the consequential cellular damage. Our results showed that BDE-209 induced matrix swelling related to MPT with 10 µM and ATP depletion with 0.1 µM. In addition, 0.5 µM BDE-209 reduced HepG2 cell viability, produced collapse of membrane potential, but increased levels of reactive oxygen species (ROS) after 48 h incubation. After 24 h with 5 µM treatment elevated levels of ROS, DNA fragmentation and cytochrome c release, accompanied by caspase 9 and caspase 3 activation was noted. Taken together, these results suggest that short-duration exposure (24 or 48 h) to 0.5 µM or 5 µM BDE-209 concentrations diminished HepG2 cell viability due to apoptosis associated with mitochondrial dysfunction.
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Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Masculino , Mitocôndrias/fisiologia , Ratos , Ratos WistarRESUMO
Introduction: Studies addressing the role of haploidentical as alternative to HLA-matched donors for stem cell transplantation (SCT) often include patients with diverse hematological malignancies in different remission statuses. Methods: We compared outcomes of children with acute lymphoblastic leukemia (ALL) undergoing SCT in second complete remission (CR2) from haploidentical (n = 25) versus HLA-matched donor (n = 51). Results: Patients were equally distributed across both groups according to age, immunophenotype, time to and site of relapse, relapse risk-group allocation, and minimal residual disease (MRD) before SCT. Incidence of graft failure, acute graft versus host disease (GVHD), and other early complications did not differ between both groups. We found no differences in overall survival (58.7% versus 59.5%; p = .8), leukemia free survival (LFS) (48% versus 36.4%; p = .5), event free survival (40% versus 34.4%; p = .69), cumulative incidence (CI) of subsequent relapse (28% versus 40.9%; p = .69), treatment related mortality (24% versus 23.6%; p = .83), CI of cGVHD (4.5% versus 18.7%; p = .2), and chronic GVHD-free and leukemia-free survival (44% versus 26.3%; p = .3) after haploidentical donor SCT. Chronic GVHD (HR = 0.09; p=.02) had protective impact, and MRD ≥ 0.01% before SCT (HR = 2.59; p=.01) had unfavorable impact on LFS. Discussion: These results support the role of haploidentical donor SCT in children with ALL in CR2.
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Cytarabine (1000 mg/m/d intravenous for 5 d) and clofarabine (40 mg/m/d intravenous for 5 d) were given every 28 days to 9 children with relapsed acute myeloid leukemia at our institution. Among 19 courses, there were 18 infectious episodes. Median hospitalization time was 13 days (7.7 to 30.5 d) per cycle. Hepatobiliary abnormalities included alanine aminotransferase/aspartate aminotransferase elevation and hyperbilirubinemia. Four patients achieved complete remission (one after an earlier allogeneic Haematopoietic Progenitor Cell Transplant). Four patients are alive disease free. In summary, a proportion of children responded and was able to receive allogeneic Haematopoietic Progenitor Cell Transplant. Side effects were tolerable, although hospitalization time was prolonged.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Criança , Pré-Escolar , Clofarabina , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Recidiva , Estudos Retrospectivos , Transplante HomólogoRESUMO
CTCF germline mutations have been related to MRD21. We report the first bilateral Wilms tumor suffered by a MRD21 patient carrying an unreported CTCF missense variant in a zinc finger domain of CTCF protein. We found that germline heterozygous variant I446K became homozygous in the tumor due to a loss of heterozygosity rearrangement affecting the whole q arm on chromosome 16. Our findings propose CTCF I446K variant as a link between MRD21 and Wilms tumor predisposition.
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Deficiência Intelectual , Neoplasias Renais , Tumor de Wilms , Humanos , Tumor de Wilms/genética , Dedos de Zinco/genética , Neoplasias Renais/genética , Células GerminativasRESUMO
Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Española de Hematología y Oncología Pediátricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP-99/SHOP-2005). In the SHOP-2005 trial, imatinib (260mg/m(2) per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6·8years, range, 1·2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non-imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow-up of 109 and 39months for the non-imatinib and imatinib cohorts, the 3-year event-free survival (EFS) was 29·6% and 78·7%, respectively (P=0·01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.
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Transplante de Células-Tronco Hematopoéticas/métodos , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/administração & dosagem , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Lactente , Masculino , Cromossomo Filadélfia , Piperazinas/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Pirimidinas/toxicidade , Espanha , Doadores de Tecidos , Transplante Homólogo , Resultado do TratamentoRESUMO
Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.
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DMT1 is a membrane-bound divalent metal transporter, which co-transports protons and (Fe(2+)) from an acidic microenvironment (endosome, duodenal lumen) to the cell cytosol. Results from animal models and from patients have shown that DMT1 is required for intestinal iron absorption and iron acquisition by erythrocytes. Only three human patients with DMT1 mutations have been described so far. They presented with hypochromic microcytic anemia and heavy liver iron overload, even at a very young age. Here, we report the fourth human case, a 7-year old boy with a new homozygous DMT1 mutation, microcytic anemia but no liver iron overload. The mutation introduces a Glycine to Arginine (p.G75R) amino acid substitution. Glycine75 is a highly conserved amino acid present in the first transmembrane domain of the protein and we hypothesize that this mutation fully impairs ferrous iron uptake from the diet and prevents the onset of liver iron overload.
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Anemia/genética , Proteínas de Transporte de Cátions/genética , Sobrecarga de Ferro/genética , Substituição de Aminoácidos , Criança , Homozigoto , Humanos , Ferro/sangue , Masculino , Mutação/genéticaRESUMO
Brominated flame retardants are used in consumer goods to increase product resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are the most commonly employed class of brominated flame retardants because they are inexpensive and can effectively prevent flame from spreading. PBDEs are persistent, can bioaccumulate, are transported over long distances, and display toxicity. However, their toxic mechanisms of action have not been well established. Because mitochondria are recognized as the main energy-producing cell organelle and play a vital role in cellular function maintenance, here we apply mitochondria as an experimental model to evaluate the toxic effects of the PBDE congener BDE-153 (Hexa-BDE) at concentrations ranging from 0.1 to 25⯵M. We also assess BDE-153 cytotoxicity to HepG2 cells in order to elucidate its mechanisms of toxicity. Exposure to BDE-153 affects isolated mitochondria: this congener can interact with the mitochondrial membrane, to dissipate the membrane potential and to induce significant ATP depletion. Furthermore, BDE-153 can diminish MTT reduction and cell proliferation and can interfere in cell cycle, as evaluated in cell cultures. These cytotoxic effects are related to mitochondrial dysfunction due to mitochondrial membrane potential dissipation and reactive oxygen species accumulation. These effects result in apoptotic cell death, as demonstrated by phosphatidylserine maintenance on the cell membrane external surface, nuclear condensation and fragmentation, and presence of pro-apoptotic factors such as cytochrome c and Apoptosis-inducing Factor (AIF) plus caspase 3 activation in the cytosol. Together, our results show PBDEs can induce cytotoxicity, reinforcing the idea that these compounds pose a risk to the exposed population.
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Apoptose/efeitos dos fármacos , Fígado/patologia , Mitocôndrias Hepáticas/patologia , Bifenil Polibromatos/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Brazil has been the largest world consumer of pesticides since 2008, followed by the USA. The herbicides trifluralin and tebuthiuron have been widely applied in agriculture. These herbicides are selective for some plant species, and their use brings various benefits. However, the genotoxic and mutagenic effects of tebuthiuron on non-target organisms are poorly known, and in addition, the effects of trifluralin must be better investigated. Therefore, this study employed genetic tests including the comet assay and micronucleus test to evaluate the genotoxic effects of trifluralin and tebuthiuron on HepG2 cells. In addition, we have used the Ames test to assess the mutagenic effects of the herbicides on the TA97a, TA98, TA100, and TA1535 strains of Salmonella typhimurium. On the basis of the comet assay and the micronucleus test, trifluralin did not cause genetic damage to HepG2 cells. In addition, trifluralin did not impact the tested S. typhimurium strains. Regarding tebuthiuron, literature has shown that this herbicide damaged DNA in Oreochromis niloticus. Nevertheless, we have found that tebuthiuron was not genotoxic to either HepG2 cells or the S. typhimurium strains. Therefore, neither trifluralin nor tebuthiuron exerted genotoxic or mutagenic potential at the tested conditions.
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Ciclídeos/genética , Compostos de Metilureia/química , Mutagênicos/farmacologia , Praguicidas/química , Salmonella typhimurium/genética , Trifluralina/química , Animais , Brasil , Ensaio Cometa , Dano ao DNA , Testes Genéticos , Células Hep G2 , Herbicidas/farmacologia , Humanos , Testes para Micronúcleos , Mutagênese , Testes de Mutagenicidade , Praguicidas/farmacologia , Salmonella typhimurium/químicaRESUMO
We describe an exceptional case of erythroid sarcoma in a pediatric patient as a growing orbital mass with no evidence of morphologic bone marrow involvement, who was finally diagnosed of pure erythroid sarcoma based on histopathology and flow cytometry criteria. We discuss the contribution of standardized eight-color flow cytometry as a rapid and reliable diagnostic method. The use of normal bone marrow databases allowed us to identify small aberrant populations in bone marrow and later confirm the diagnosis in the neoplastic tissue.
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The RUNX1 (alias AML1) gene is involved in several patterns of chromosomal translocations and rearrangements associated with human acute leukemia. Often, multiple signals for AML1 have been observed in childhood acute lymphoblastic leukemia (ALL) due to frequent polysomy of chromosome 21 in this leukemia. Additionally, high-level amplification of AML1, in the absence of polysomy of chromosome 21, has been reported in childhood ALL. We report two new cases of childhood ALL, without a ETV6/RUNX1 (alias TEL/AML1) rearrangement, showing high-level amplification of the AML1 gene detected by fluorescence in situ hybridization and comparative genomic hybridization analysis. The first case was an 11-year-old girl with 7-12 signals for AML1 in nearly 84% of the cells, and the loss of a TEL allele. In the second patient, a 6-year-old girl, multiple copies of the AML1 gene were also observed in 99% of the cells, although no deletion of TEL was found. The similarity in the clinicobiologic features of all the cases with this abnormality points to an emerging molecular cytogenetic subgroup of B-cell precursor ALL and suggests a possible dosage effect of AML1 in the pathogenesis of leukemia.
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Subunidade alfa 2 de Fator de Ligação ao Core/genética , Amplificação de Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Feminino , Humanos , Hibridização in Situ FluorescenteRESUMO
Apoptotic cell death is one of the main consequences of exposure to brominated flame retardants, including polybrominated diphenyl ethers. However, few of these compounds have had their potential toxicity investigated. BDE-154 is one of the most poorly studied polybrominated diphenyl ether (PBDE) congeners, but its level in the environment and in biological fluids is rising. In addition, its chemical structure differs from the other congeners with well-documented toxicity, so BDE-154 may display a distinct toxicity pattern. This study has evaluated how BDE-154 affects the human hepatoblastoma cell line (HepG2) and has looked into the impact of this congener on human health. In addition, this study has related the effects of BDE-154 with the effects of BDE-47 to clarify the mechanism of PBDE toxicity. The HepG2 cell line was exposed to BDEs for 24 and 48 hr and submitted to assays to examine proliferation, viability, mitochondrial membrane potential, reactive oxygen species accumulation, phosphatidylserine exposure, nuclear fragmentation and evaluation of pro-caspase 3, pro-caspase 9, cytochrome c release, and apoptosis inductor factor release by Western blot analysis. BDE-154 induced mitochondrial damage and led to apoptotic death of HepG2 cells, but these effects were less intense than the effects promoted by BDE-47. Unlike other extensively reported congeners, BDE-154 was only toxic at the higher tested concentrations, whereas BDE-47 cytotoxicity was evident even at lower concentrations. Hence, like the toxicity pattern of other classes of substances such as polychlorinated biphenyls, the toxicity pattern of BDEs also depends on their chemical structure and aromatic substituent.
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Apoptose/efeitos dos fármacos , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Fator de Indução de Apoptose/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Citocromos c/metabolismo , Células Hep G2 , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Indiscriminate use of synthetic substances has led to environmental contamination and increasing human and animal exposure to harmful chemicals. Polybrominated flame retardants (PBDEs), which serve as non-covalent additives that enhance the safety of a variety of commercial and consumer goods, are an important class among potentially damaging synthetic substances. Its use is very common in developing countries, including Brazil. In theory, 209 different PBDE congeners exist, and many are currently being used during the manufacture of several products. Unfortunately, PBDEs are easily released from the original products, promptly reaching the environment. Knowledge about the toxicological power of these substances is still limited, which has prevented environmental and regulatory authorities from conducting adequate risk assessments. This research addresses the genotoxic and mutagenic potential of PBDEs. The effects of HepG2 cells and Salmonella typhimurium exposure to six main representatives of PBDEs, namely tetrabromodiphenyl ether (BDE-47), pentabromodiphenyl ether (BDE-99 and BDE-100), hexabromodiphenyl ether (BDE-153 and BDE-154) and decabromodiphenyl ether (BDE-209), were evaluated. The comet assay revealed that all the assessed BDEs exerted genotoxic effects but induced no micronuclei formation in HepG2 cells. These BDEs had no significant mutagenic effects on the Salmonella typhimurium strains TA98 and TA100. Taken together, the results of the genomic instability assays showed that PBDEs can represent a risk to the health of directly and indirectly exposed population, because the assessed BDEs induce genotoxic effects in the HepG2 cell line.
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Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Mutagênicos/toxicidade , Ensaio Cometa , Poluentes Ambientais/química , Éteres Difenil Halogenados/química , Células Hep G2 , Humanos , Isomerismo , Testes para Micronúcleos , Peso Molecular , Testes de Mutagenicidade , Mutagênicos/química , Concentração Osmolar , Bifenil Polibromatos/química , Bifenil Polibromatos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Solubilidade , Temperatura de TransiçãoRESUMO
Technological, agricultural, and medical advances have improved the lifestyle of humankind. However, these advances have caused new problems that affect the environment and future generations. Emerging contaminants display properties such as low degradation potential and environmental persistence. In addition, most contaminants are lipophilic, which culminates in high bioaccumulation. The disposal of pharmaceuticals and personal care products into the environment underlies microbial and bacterial resistance. Plasticizers change several characteristics of industrialized materials, such as flexibility, but they are potentially carcinogenic and disrupt the endocrine system. Pesticides prevent the propagation of numerous kinds of pests; nevertheless, they exert neurotoxic and mutagenic effects, and they impact the environment negatively. Addition of flame retardants to a number of materials prevents flame propagation; however, after their release into the environment, these chemicals may bioaccumulate in organisms and disrupt the endocrine system, too. Surfactants can change the surface and interfacial properties of liquids, but their presence in the environment can interfere with countless enzymes and can even impair the endocrine system of various organisms and induce the feminization of species. Hence, gaining knowledge about emerging contaminants is increasingly important to minimize future damage and enable proper monitoring of each class of compounds in the environment which will help to improve legislation on this matter.
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Meio Ambiente , Poluentes Ambientais/toxicidade , Saúde , Animais , Ecotoxicologia , Humanos , RiscoRESUMO
Stage 4S neuroblastoma is a disease associated with spontaneous regression and good survival. We present a patient whose evolution has shown the variety and complexity of this disease in infants. Biologic factors, such as ploidy, MYCN copy number, loss of 1p36, and other chromosomal gains and losses were determined. A complex pattern of genetic abnormalities, such as near-diploidy, MYCN gain (2-4 copies per haploid genome) and imbalance/deletion of 1p36 was seen in the diagnostic sample. An extensive disseminated disease after a latent period of 26 months was associated with a special genetic evolution, such a tetraploidy, MYCN amplification (2:100-500 copies), 1p36 deletion, and gain of 17q. Our results provide evidence that either the primary tumor was heterogeneous in terms of gene amplification or that amplification was acquired later on as a transition from MYCN gain. We suggest that near-di-/tetraploid 4S tumors with MYCN gain and/or deletion 1p could be progressing 4S tumors.
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Neoplasias das Glândulas Suprarrenais/genética , Amplificação de Genes , Genes myc , Neuroblastoma/genética , Neoplasias das Glândulas Suprarrenais/patologia , Aneuploidia , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 17/genética , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/patologiaRESUMO
This study uses statistical techniques to evaluate reports on suicide scenes; it utilizes 80 reports from different locations in Brazil, randomly collected from both federal and state jurisdictions. We aimed to assess a heterogeneous group of cases in order to obtain an overall perspective of the problem. We evaluated variables regarding the characteristics of the crime scene, such as the detected traces (blood, instruments and clothes) that were found and we addressed the methodology employed by the experts. A qualitative approach using basic statistics revealed a wide distribution as to how the issue was addressed in the documents. We examined a quantitative approach involving an empirical equation and we used multivariate procedures to validate the quantitative methodology proposed for this empirical equation. The methodology successfully identified the main differences in the information presented in the reports, showing that there is no standardized method of analyzing evidences.
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Medicina Legal/métodos , Medicina Legal/estatística & dados numéricos , Modelos Estatísticos , Suicídio , Brasil , Análise por Conglomerados , Humanos , Análise dos Mínimos Quadrados , Análise de Componente Principal , Relatório de PesquisaRESUMO
BACKGROUND AND OBJECTIVES: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. PATIENTS AND METHODS: Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. RESULTS: A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (10(9)/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×10(9)/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). CONCLUSIONS: Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact.