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1.
Urologe A ; 60(9): 1159-1166, 2021 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-34255127

RESUMO

In the context of cancer surgery, there is always a trade-off between oncological safety and preservation of function. This is especially true in pelvic surgery due to the close relationship to the pelvic floor muscles, blood supply and nerves. Currently, risk models, preoperative imaging, the surgeon's assessment, and the intraoperative frozen section serve as the basis for decision-making. New imaging techniques and standardization in frozen section have significantly improved this in recent years. However, limitations remain due to time delays as well as more difficult correct anatomical assignment in the follow-up. Alternative intraoperative techniques may overcome this limitation in the future. Patient-derived organoids have emerged as an important new research vehicle in recent years. They are based on tumor stem cells that, under special culture conditions, form three-dimensional replicas of the original tissue. This makes them ideally suited for testing individual system therapies but also as a validation technique for new intraoperative diagnostic procedures. The Research Training Group 2543/I, which is funded by the German Research Foundation, is researching the potential of new diagnostic methods in an interdisciplinary team regarding validation in addition to intraoperative frozen sections.


Assuntos
Secções Congeladas , Organoides , Humanos , Pelve
2.
Physiotherapy ; 101(1): 50-4, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25282389

RESUMO

BACKGROUND: Patients' subjective impression of change is an important construct to measure following physiotherapy, but little evidence exists about the best type of measure to use. OBJECTIVE: To compare the construct validity and utility of two forms of a global subjective outcome scale (GSOS) in patients with back pain: Likert and visual analogue scale (VAS) GSOS. DESIGN: Two samples of patients attending physiotherapy for back pain completed a questionnaire battery at discharge from physiotherapy including either a Likert or VAS GSOS. PARTICIPANTS: One hundred and eighty-seven {79 males, mean age 52.1 [standard deviation (SD) 15.5] years} patients completed the Likert GSOS and a separate sample of 144 patients [62 males, mean age 55.7 (SD 15.9) years] completed the VAS GSOS upon discharge from physiotherapy. MAIN COMPARISONS: The two versions of the GSOS were compared using pre- and post-treatment changes in scores using a VAS (pain), Roland-Morris Disability Questionnaire (18-item version) and catastrophising subscale of the Coping Strategies Questionnaire 24. RESULTS: Both versions of the GSOS showed significant (P<0.01) moderate correlations (r between 0.30 and 0.46) with changes in pain and disability. The correlations between the two types of GSOS and changes in catastrophising were trivial and not significant (Likert GSOS: r=0.07, P=0.372; VAS GSOS: r=0.10, P=0.267). There were fewer missing values in the Likert GSOS (1%) compared with the VAS GSOS (8%). CONCLUSIONS: The two versions of the GSOS showed similar validity; however, use of the Likert GSOS is recommended because of its greater utility.


Assuntos
Avaliação da Deficiência , Dor Lombar/diagnóstico , Dor Lombar/reabilitação , Medição da Dor/instrumentação , Satisfação do Paciente/estatística & dados numéricos , Escala Visual Analógica , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Medição da Dor/métodos , Modalidades de Fisioterapia , Reprodutibilidade dos Testes , Medição de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento
3.
Br J Haematol ; 168(4): 533-46, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25308804

RESUMO

Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 10(9) /l) comprise a unique subset of high-risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group-1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post-induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 × 10(9) /l (5-year event-free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B-ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B-ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucocitose/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Irradiação Craniana , Ciclofosfamida/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Idarubicina/administração & dosagem , Lactente , Estimativa de Kaplan-Meier , Leucemia de Células B/sangue , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/mortalidade , Leucemia de Células B/radioterapia , Contagem de Leucócitos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/radioterapia , Prednisona/administração & dosagem , Indução de Remissão , Risco , Resultado do Tratamento , Vincristina/administração & dosagem
4.
Lancet Oncol ; 13(9): 906-15, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22901620

RESUMO

BACKGROUND: Acute lymphoblastic leukaemia (ALL) is curable in more than 80% of children and adolescents who exhibit high-risk features. However, treatments are associated with symptomatic osteonecrosis that disproportionately affects adolescents. Based on the findings from the CCG-1882 trial, the CCG-1961 trial was designed to assess whether dexamethasone dose modification would reduce the risk of osteonecrosis. We therefore compared use of continuous versus alternate-week dexamethasone within standard and intensified post-induction treatments. METHODS: In the CCG-1961 trial, a multicohort cooperative group trial, 2056 patients (aged 1-21 years) with newly diagnosed high-risk ALL (age ≥10 years, white blood cell count ≥50×10(9) per L, or both) were recruited. To address osteonecrosis, a novel alternate-week schedule of dexamethasone (10 mg/m(2) per day on days 0-6 and 14-20) was compared with standard continuous dexamethasone (10 mg/m(2) per day on days 0-20) in computer-generated randomised regimens with permuted blocks within double or single delayed intensification phases, respectively. Masking was not possible because of the differences in the treatments. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002812. FINDINGS: Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. In patients aged 1-21 years, the overall cumulative incidence of osteonecrosis at 5 years was 7·7% (SE 0·9), correlating with age at ALL diagnosis (1-9 years, 1·0% [0·5]; 10-15 years, 9·9% [1·5], hazard ratio 10·4 [4·8-22·5]; 16-21 years, 20·0% [4·3], 22·2 [10·0-49·3]; p<0·0001) and sex of the patients aged 10-21 years (girls 15·7% [2·5] vs boys 9·3% [1·7], 1·7 [1·2-2·4]; p=0·001). For patients aged 10 years and older with a rapid response to induction treatment, the use of alternate-week dexamethasone during phases of delayed intensification significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7% [2·1] vs 17·0% [2·9], 2·1 [1·4-3·1]; p=0·0005), especially in those aged 16 years and older (11·3% [5·3] vs 37·5% [11·0], p=0·0003; girls 17·2% [8·1] vs 43·9% [14·1], p=0·05; boys 7·7% [5·9] vs 34·6% [11·6], p=0·0014). INTERPRETATION: Alternate-week dexamethasone during delayed intensification phases, a simple dose modification, reduces the risk of osteonecrosis in children and adolescents given intensified treatment for high-risk ALL. Its use is being evaluated in children with standard risk ALL. FUNDING: US National Cancer Institute at the National Institutes of Health.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Osteonecrose/induzido quimicamente , Osteonecrose/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Incidência , Lactente , Masculino , Metotrexato/administração & dosagem , Osteonecrose/diagnóstico , Osteonecrose/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Distribuição por Sexo , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto Jovem
5.
Leuk Lymphoma ; 49(6): 1142-54, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18569638

RESUMO

The Children's Cancer Group initiated risk-based allocation for childhood acute lymphoblastic leukemia 3 decades ago. Long-term survival data (minimum follow-up >10 years) is now available. About 3711 eligible children were enrolled in risk-adjusted treatment protocols (1983-1989). Ten-year event-free survival (EFS) and overall survival were 62% (standard deviation [SD] = 1%) and 73% (SD = 1%). These data showed a significant improvement (P < 0.0001) compared with the predecessor studies. Since 11% of patients with initial relapses survived without second events, these data predicted a cure rate of 73%. Ten-year EFS and survival were improved significantly for patients with intermediate risk (P < 0.0001), high risk (P < 0.0001) and lymphomatous features (P < 0.0001). Key components of therapies included delayed intensification and substitution of intrathecal chemotherapy for prophylactic/preventive cranial radiation in low- and intermediate-risk patients. This is the largest series of children on concurrent studies who were observed more than 10 years.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Criança , Terapia Combinada , Irradiação Craniana , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
6.
Blood ; 111(9): 4496-9, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18285546

RESUMO

As glucocorticoid use increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. Besides increased age, host risk factors are poorly defined. We tested whether 12 polymorphisms were associated with osteonecrosis among patients 10 years and older treated on the CCG1882 protocol. Candidate genes (TYMS, MTHFR, ABCB1, BGLAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, and PTHR) were chosen based on putative mechanisms underlying osteonecrosis risk. All children received dexamethasone, with doses varying by treatment arm. A PAI-1 polymorphism (rs6092) was associated with risk of osteonecrosis in univariate (P = .002; odds ratio = 2.79) and multivariate (P = .002; odds ratio = 2.89) analyses (adjusting for gender, age, and treatment arm). Overall, 21 of 78 (26.9%) children with PAI-1 GA/AA genotypes, versus 25 of 214 (11.7%) children with GG genotype, developed osteonecrosis. PAI-1 polymorphisms and PAI-1 serum levels have previously been associated with thrombosis. We conclude that PAI-1 genetic variation may contribute to risk of osteonecrosis.


Assuntos
Osteonecrose/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Adulto , Análise de Variância , Criança , Análise Mutacional de DNA , Dexametasona/efeitos adversos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Osteonecrose/etiologia , Valor Preditivo dos Testes
7.
Blood ; 111(5): 2548-55, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18039957

RESUMO

Longer and more intensive postinduction intensification (PII) improved the outcome of children and adolescents with "higher risk" acute lymphoblastic leukemia (ALL) and a slow marrow response to induction therapy. In the Children's Cancer Group study (CCG-1961), we tested longer versus more intensive PII, using a 2 x 2 factorial design for children with higher risk ALL and a rapid marrow response to induction therapy. Between November 1996 and May 2002, 2078 children and adolescents with newly diagnosed ALL (1 to 9 years old with white blood count 50 000/mm3 or more, or 10 years of age or older with any white blood count) were enrolled. After induction, 1299 patients with marrow blasts less than or equal to 25% on day 7 of induction (rapid early responders) were randomized to standard or longer duration (n = 651 + 648) and standard or increased intensity (n = 649 + 650) PII. Stronger intensity PII improved event-free survival (81% vs 72%, P < .001) and survival (89% vs 83%, P = .003) at 5 years. Differences were most apparent after 2 years from diagnosis. Longer duration PII provided no benefit. Stronger intensity but not prolonged duration PII improved outcome for patients with higher-risk ALL. This study is registered at http://clinicaltrials.gov as NCT00002812.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
8.
Blood ; 109(3): 926-35, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17003380

RESUMO

The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Adolescente , Adulto , Algoritmos , Biomarcadores , Criança , Pré-Escolar , Classificação , Análise Citogenética , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento
9.
Blood ; 106(13): 4043-9, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16109782

RESUMO

We assessed the outcome of children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) receiving contemporary risk-based therapy by evaluating clinical and biologic features and outcome of children with ALL, with or without DS, enrolled in Children's Cancer Group (CCG) protocols between 1983 and 1995. Comparison of characteristics of children with ALL with (ALL-DS; n = 179) or without (ALL-NDS; n = 8268) DS showed no differences in initial white blood cell (WBC) count, central nervous system disease, and risk group. Children with ALL-DS did not present with unfavorable translocations and were older than 1 year of age at diagnosis with ALL. Event-free (56% vs 74%; P < .001) and disease-free (55% vs 73%; P < .001) survival at 10 years was significantly lower in the standard-risk ALL-DS population compared with ALL-NDS, but not in high-risk ALL-DS population (event-free survival, 62% vs 59%; P = .9; disease-free survival, 64% vs 59%; P = .9), and these differences persisted regardless of treatment era (early era [1983-1989] vs recent era [1989-1995]). Multivariate analysis revealed that presence of DS demonstrated an independent significant adverse prognostic effect for the standard-risk population, but not for the high-risk patients. These results suggest that intensification of therapy for patients with ALL-DS is needed to maintain outcome comparable with those of ALL-NDS patients.


Assuntos
Síndrome de Down/patologia , Síndrome de Down/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Síndrome de Down/complicações , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Recidiva , Fatores de Risco , Resultado do Tratamento
11.
Pediatr Blood Cancer ; 44(1): 21-8, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15368546

RESUMO

BACKGROUND: Patients with Down syndrome (DS) and standard risk (SR) acute lymphoblastic leukemia (ALL-DS) are reported to have inferior event free (EFS) and overall survival (OS) compared to patients without DS (ALL-NDS). PROCEDURE: We compared the prevalence of favorable and unfavorable clinical and biologic features, toxicity and outcome within the ALL-DS and ALL-NDS cohorts of 2,174 eligible patients with SR-ALL enrolled on CCG-1952. RESULTS: Fifty-nine patients (3%) had ALL-DS. DS patients were less likely to have either favorable (hyperdiploidy, triple trisomy of chromosomes 4, 10, and 17, TEL-AML1 rearrangement) or unfavorable (T-cell ALL, hypodiploidy, adverse translocations) biologic features. Toxicity occurred significantly more often and number of days hospitalized was significantly greater in ALL-DS than in ALL-NDS. ALL-DS patients had an inferior 4-year EFS compared to the NDS cohort. However, EFS was equivalent when the comparison excluded ALL-NDS with favorable biologic features. OS was significantly inferior for ALL-DS. CONCLUSIONS: The absence of favorable biologic features within ALL-DS contributes to the difference in EFS previously observed between DS and NDS SR-ALL cohorts.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndrome de Down/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Prognóstico , Resultado do Tratamento
12.
Pediatr Blood Cancer ; 45(1): 5-9, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15481062

RESUMO

PURPOSE: To compare outcomes of patients with NCI standard risk acute lymphoblastic leukemia (ALL) who relapsed after being randomized to receive either oral or intravenous 6-mercaptopurine (6MP) in the Children's Cancer Group study CCG 1922. PATIENTS AND METHODS: CCG 1922 accrued patients from March 1993 to August 1995. A total of 1,060 patients were randomly assigned to four treatment groups: oral 6MP plus prednisone (OP), intravenous 6MP plus prednisone (IP), oral 6MP plus dexamethasone (OD), and intravenous 6MP plus dexamethasone (ID). During the 2nd through 4th month of therapy groups OP and OD were treated with 75 mg/m(2)/day of oral 6MP for 70 days and groups IP and ID with 1,000 mg/m(2)/week of intravenous 6MP over 10 hr for 11 doses. All patients received a single delayed intensification and all received oral 6MP in maintenance. RESULTS: Patients randomized to oral 6MP had significantly better 5-year overall survival (96 +/- 1% vs. 92 +/- 1%; P = 0.008). There was, however, no statistically significant difference in the event-free survival (EFS). Of the 179 patients who relapsed, 84 had a second or later event and 68 have died. Forty of the 84 second events were a death. Survival after relapse was significantly greater for patients randomized to oral 6MP during consolidation than those receiving intravenous 6MP (P = 0.002, log rank test) with 4-year survival post-relapse of 67 +/- 6% vs. 48 +/- 6%. The steroid randomization had no influence on outcome. Post-relapse therapy details are not available and if different between groups may have influenced the outcome. CONCLUSION: Treatment with intravenous 6MP during a brief period of total therapy had a significant negative impact on the prognosis in childhood ALL even though oral 6MP was used during maintenance.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Mercaptopurina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Terapia de Salvação , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Intervalo Livre de Doença , Humanos , Lactente , Infusões Intravenosas , Tábuas de Vida , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Taxa de Sobrevida
13.
J Pediatr Hematol Oncol ; 25(9): 688-95, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12972803

RESUMO

PURPOSE: Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. METHODS: Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. RESULTS: Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. CONCLUSIONS: These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Proteínas de Transporte/biossíntese , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/farmacocinética , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Superfície Celular , Tetra-Hidrofolato Desidrogenase/biossíntese , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transporte Biológico , Proteínas de Transporte/genética , Criança , Pré-Escolar , Intervalo Livre de Doença , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Receptores de Folato com Âncoras de GPI , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Células-Tronco Neoplásicas/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Antígeno Nuclear de Célula em Proliferação/análise , Tetra-Hidrofolato Desidrogenase/genética
14.
Blood ; 101(10): 3809-17, 2003 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12531809

RESUMO

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse.


Assuntos
Dexametasona/uso terapêutico , Mercaptopurina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prednisona/uso terapêutico , Administração Oral , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Lactente , Injeções Intravenosas , Injeções Espinhais , Cariotipagem , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prednisona/administração & dosagem , Prednisona/efeitos adversos
15.
Blood ; 100(6): 1957-64, 2002 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12200352

RESUMO

Black children with acute lymphoblastic leukemia (ALL) have poor outcomes, but limited information is available for children from other racial and ethnic backgrounds, such as Hispanic and Asian. We undertook a retrospective cohort study of children with ALL treated on Children's Cancer Group therapeutic protocols to determine outcomes by racial and ethnic backgrounds of patients treated with contemporary risk-based therapy. In total, 8447 children (white, n = 6703; Hispanic, n = 1071; black, n = 506; and Asian, n = 167) with newly diagnosed ALL between 1983 and 1995 were observed for a median of 6.5 years. Analysis of disease outcome was measured as overall survival (OS) and event-free survival (EFS) and was adjusted for known predictors of outcome including clinical features, disease biology, socioeconomic status, and treatment era (1983-1989 vs 1989-1995). There was a statistically significant difference in survival by ethnicity (P <.001). Five-year EFS rates were: Asian, 75.1% +/- 3.5%; white, 72.8% +/- 0.6%; Hispanic, 65.9% +/- 1.5%; and black, 61.5% +/- 2.2%. Multivariate analysis revealed that when compared with white children, black and Hispanic children had worse outcomes and Asian children had better outcomes after adjusting for known risk factors. The poorer outcomes among black children were most apparent among patients with standard-risk features (relative risk [RR], 2.0; 95% confidence interval [CI], 1.6-2.5), whereas poorer outcomes in Hispanic children (RR, 1.4; 95% CI, 1.2-1.6) were most evident among patients with high-risk features. Asian children had better outcomes than all racial and ethnic groups among high-risk patients, particularly in the recent era (5-year EFS, 90.9% +/- 6.1%). Racial and ethnic differences in OS and EFS persist among children with ALL who receive contemporary risk-based therapy. Future studies should focus on reasons-perhaps compliance or pharmacogenetics-for those differences.


Assuntos
Etnicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Grupos Raciais , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Classe Social , Análise de Sobrevida , Resultado do Tratamento
16.
Blood ; 99(12): 4257-64, 2002 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12036851

RESUMO

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.


Assuntos
Segunda Neoplasia Primária/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Análise Atuarial , Criança , Pré-Escolar , Estudos de Coortes , Irradiação Craniana/efeitos adversos , Feminino , Seguimentos , Humanos , Incidência , Masculino , Análise Multivariada , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Doses de Radiação , Recidiva , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida
17.
Cancer ; 94(4): 1102-10, 2002 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11920481

RESUMO

BACKGROUND: Recurring breakpoints in chromosome bands 15q13-15 occur infrequently in leukemia. To the authors' knowledge, the clinical significance of these breakpoints in childhood acute lymphoblastic leukemia (ALL) has not been previously investigated. METHODS: Centrally reviewed karyotypes of children with newly diagnosed ALL enrolled on Children's Cancer Group protocols from 1988 to 1995 formed the basis of the current report. Statistical analyses used chi-square tests for homogeneity of proportions, and outcome was analyzed using life table methods and associated statistics. RESULTS: Of 1946 cases with centrally reviewed and accepted cytogenetic analyses, 23 cases (1%) had breakpoints in chromosome bands 15q13-15. Most patients with 15q13-15 breakpoints had standard risk ALL, although breakpoints in 15q13-15 occurred more frequently in infants than in older children. The majority of these patients (16 patients; 70%) had balanced 15q13-15 rearrangements. Additional chromosomal abnormalities not involving 15q included abnormal 12p, abnormal 9p, Philadelphia chromosome, deletion 6q, and an 11q23 breakpoint. Thirteen (57%) 15q13-15 breakpoints occurred in pseudodiploid karyotypes; five (22%) were in hyperdiploid karyotypes with 47-50 chromosomes; two (9%) were in hyperdiploid karyotypes with > 50 chromosomes; and three (13%) were in hypodiploid karyotypes. Of the 23 patients with 15q13-15 breakpoints, 21 were survivors, 18 survived event-free for 2.2-9.3 years, and 3 were alive 1 to 3 years after a relapse at time of writing. CONCLUSIONS: The current study suggests that genes at 15q13-15 may be involved in the leukemogenesis of some cases of childhood ALL, but that with current intensive therapy such aberrations do not confer increased risk of treatment failure.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 15/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transformação Celular Neoplásica , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Cariotipagem , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia
18.
Blood ; 99(3): 825-33, 2002 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11806983

RESUMO

Addition of a delayed-intensification (DI) phase after standard induction/consolidation therapy was previously shown to improve outcome for patients younger than 10 years of age with intermediate-risk acute lymphoblastic leukemia (ALL). The current trial randomized 1204 patients to regimens containing a single DI phase (405 patients), 2 DI phases (DDI) (402 patients), or a single DI phase in conjunction with increased vincristine and prednisone pulses during maintenance (DIVPI) (397 patients). Estimates of event-free survival (EFS) and survival at 6 years are 79% +/- 1% and 89% +/- 1%, respectively. EFS was improved on DDI compared with either DI (log-rank P =.04; Kaplan-Meier [KM] P =.04; relative risk [RR] = 1.38) or DIVPI (log-rank P =.04; KM P =.01; RR = 1.39). There was no difference in EFS for the DI and DIVPI regimens (log-rank P =.96; KM P =.75). Survival estimates at 6 years were 87% (SD = 2%) for DI; 91% (SD = 2%) for DDI; and 90% (SD = 2%) for DIVPI (P =.17). Significant univariate risk factors for the overall cohort included poor day-7 marrow response, black race, and age of at least 5 years. These data demonstrate that DDI improves EFS of patients younger than 10 years of age with intermediate-risk ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Hemoglobinas/metabolismo , Humanos , Lactente , Masculino , Grupos Raciais , Fatores de Risco , Esplenomegalia , Resultado do Tratamento
19.
J Acoust Soc Am ; 109(4): 1417-21, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11325113

RESUMO

The transmission of waves through two discontinuities in a one-dimensional waveguide system is considered. Attention is focused on transmission through a structural insert, which is defined here to be a waveguide segment which is inserted into an otherwise continuous structural member with different properties. A general expression for the net transmission through the insert is found. It has bandpass/stop characteristics and its frequency average is somewhat greater than that normally assumed due to the coherent interaction of the waves in the insert. The particular case is then considered where the insert comprises a three-layer composite beam inserted in a thin beam which vibrates in bending. The composite beam comprises two elastic faceplates and a core filled with a tunable electro- or magneto-rheological fluid. The net transmission and the stop bands depend on the properties of the insert. Since these properties are tunable by adjusting the field to which the tunable fluid is exposed, then so too are the transmission characteristics of the insert.

20.
J Appl Bacteriol ; 74(5): 526-31, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-7683638

RESUMO

23S ribosomal RNa (rRNA) gene sequences of Streptococcus uberis and Strep. parauberis were determined by direct polymerase chain reaction (PCR) sequencing. Oligonucleotide probes specific for Strep. uberis and Strep. parauberis were designed from variable regions of the 23S rRNA gene sequence data. Molecular hybridizations with PCR-amplified rRNA gene targets provided a precise and reliable means of differentiating Strep. uberis and Strep. parauberis from each other and from other streptococcal species.


Assuntos
DNA Ribossômico/genética , Sondas de Oligonucleotídeos , RNA Bacteriano/genética , RNA Ribossômico 23S/genética , Streptococcus/classificação , Técnicas de Tipagem Bacteriana , Sequência de Bases , DNA Bacteriano/genética , Genes Bacterianos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase , Streptococcus/genética
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