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1.
Haematologica ; 107(10): 2295-2303, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35112552

RESUMO

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Alanina Transaminase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida/uso terapêutico , Etoposídeo , Humanos , Inibidores de MTOR , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Fosfoproteínas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR
2.
Am J Hematol ; 97(5): 613-622, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35180323

RESUMO

Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1-20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m2 . The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p < .001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations.


Assuntos
Leucemia Mieloide Aguda , Linfoma , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Citarabina , Decitabina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Linfoma/tratamento farmacológico , Vorinostat
3.
Pediatr Radiol ; 50(4): 524-533, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31776602

RESUMO

BACKGROUND: Altered biodistribution of [F-18]2-fluoro-2-deoxyglucose (FDG) is sometimes encountered in pediatric patients undergoing chemotherapy for lymphoma on post-induction positron emission tomography (PET) imaging. A characteristic pattern of increased FDG uptake in white adipose tissue can be seen, particularly in the buccal regions, body wall and gluteal regions, with a shift of radiotracer away from the blood pool and liver. This altered biodistribution has been attributed to effects of corticosteroids in pediatric and adult patients and is important to recognize because of its potential for limiting the diagnostic quality of the PET scan and interfering with therapeutic response assessment. OBJECTIVE: In contrast to the well-known metabolically active brown fat seen on up to one-third of pediatric PET scans, white fat is usually non-metabolically active. We sought to determine the incidence of altered distribution of FDG in subcutaneous white adipose tissue in pediatric patients undergoing PET imaging and to assess the association with corticosteroid use. MATERIALS AND METHODS: We reviewed the medical records and imaging for four children in whom altered biodistribution in white adipose tissue was present on post-induction FDG PET/CT, identified during routine clinical practice. All four were receiving corticosteroids as part of their chemotherapy. We then retrospectively reviewed oncology FDG PET/CT scans over a 2-year period (1,361 scans in 689 patients) to determine the incidence of uptake in white fat by qualitative visual assessment. In the children identified with altered biodistribution, we measured maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean) in areas of subcutaneous white fat, the buccal regions, body wall or gluteal soft-tissue regions, liver and blood pool. We reviewed all medical records, including medication lists. We summarize the relevant clinical and imaging findings of 13 pediatric patients, including the 4 index patients. RESULTS: We determined the incidence of FDG uptake in white fat to be rare, found in 9 of 1,361 (0.6%) PET scans performed for pediatric cancer evaluation. FDG uptake was increased in subcutaneous adipose tissue, particularly in the buccal regions, body wall and gluteal regions, with a shift of radiotracer away from the blood pool and liver. The degree of increased uptake in peripheral white fat varied from marked to mild, and the biodistribution was distinct from that of brown adipose tissue. Children with this altered biodistribution were uniformly receiving corticosteroids as part of induction treatment for their cancer, and these findings were only identified on post-induction PET/CT. Follow-up PET/CT documented resolution of this effect after treatment with corticosteroids ceased. CONCLUSION: Our findings support the current understanding that characteristic uptake of FDG in white adipose tissue is mediated by corticosteroid effect. Although this altered biodistribution is rare (<1% of PET scans) it could impair the diagnostic quality of the scan, affecting image interpretation, and should be recognized when present.


Assuntos
Tecido Adiposo Branco/metabolismo , Fluordesoxiglucose F18/farmacocinética , Linfoma/diagnóstico por imagem , Linfoma/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/farmacocinética , Adolescente , Corticosteroides/uso terapêutico , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos
4.
AJR Am J Roentgenol ; 212(2): 456-460, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30476458

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the clinical utility of Deauville scores in interpretation of end-of-chemotherapy FDG PET scans. CONCLUSION: Deauville scores improve the clinical utility of end-of-chemotherapy PET, as evidenced by an increase in positive predictive value to 72.7% from 44.4% on the basis of report alone. The negative predictive value remains greater than 95%.


Assuntos
Fluordesoxiglucose F18 , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/epidemiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
5.
J Pediatr Hematol Oncol ; 40(6): 483-486, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29200166

RESUMO

Immune dysregulation and predisposition to malignancies are critical comorbidities in children affected with ataxia telangiectasia. In addition, these children exhibit increased toxicity to conventional cancer therapy and dose reductions have been proposed to prevent life threatening adverse effects. These modifications to the treatment regimen may result in suboptimal outcomes for these patients. Our report of 3 children with ataxia telangiectasia and cancer highlight the immense challenges in the management of these children, underlining the need for the development of novel, biological agents with reduced acute and long-term side effects in the treatment of cancers in these children.


Assuntos
Lesões Pré-Cancerosas , Ataxia Telangiectasia/imunologia , Ataxia Telangiectasia/patologia , Ataxia Telangiectasia/terapia , Criança , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/prevenção & controle
6.
J Med Philos ; 42(1): 7-32, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28064253

RESUMO

The Belmont Report's distinction between research and the practice of accepted therapy has led various authors to suggest that these purportedly distinct activities should be governed by different ethical principles. We consider some of the ethical consequences of attempts to separate the two and conclude that separation fails along ontological, ethical, and epistemological dimensions. Clinical practice and clinical research, as with yin and yang, can be thought of as complementary forces interacting to form a dynamic system in which the whole exceeds the sum of its parts. Just as effective clinical practice cannot exist without clinical research, meaningful clinical research requires the context of clinical practice. We defend this thesis by triangulation, that is, by outlining how multiple investigators have reached this conclusion on the basis of varied theoretical and applied approaches. More confidence can be placed in a result if different methods/viewpoints have led to that result.


Assuntos
Pesquisa Biomédica/ética , Atenção à Saúde/ética , Ensaios Clínicos como Assunto/ética , Pesquisa sobre Serviços de Saúde/ética , Humanos , Filosofia Médica , Pesquisadores/psicologia
7.
J Peripher Nerv Syst ; 20(1): 37-46, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25977177

RESUMO

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Vincristina/efeitos adversos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Medição da Dor , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Índice de Gravidade de Doença
9.
JAMA ; 314(9): 913-25, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26325560

RESUMO

IMPORTANCE: Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. OBJECTIVE: To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer. EXPOSURES: Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians. MAIN OUTCOMES AND MEASURES: Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer. RESULTS: Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening. CONCLUSIONS AND RELEVANCE: In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.


Assuntos
Aconselhamento Genético , Neoplasias/genética , Análise de Sequência de DNA/métodos , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Família , Estudos de Viabilidade , Fusão Gênica , Neoplasias Hematológicas/genética , Humanos , Achados Incidentais , Lactente , Recém-Nascido , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/genética , Neoplasias/terapia , Avaliação de Resultados em Cuidados de Saúde , Indução de Remissão , Adulto Jovem
10.
Clin J Pain ; 39(7): 326-333, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37083638

RESUMO

OBJECTIVES: Some patients with sickle cell disease (SCD) have features of nociplastic pain. While research suggests that many patients with nociplastic pain consume more opioids due to opioid nonresponsiveness, little is known about the impact of nociplastic pain and pain catastrophizing on opioid consumption and pain interference among adolescents and young adults (AYA) with SCD. The purpose of this study was to (1) characterize nociplastic pain and pain catastrophizing among AYA with SCD, and (2) determine whether these characterizations are associated with subsequent opioid consumption and pain interference 1 month after characterization. METHODS: Participants completed surveys characterizing nociplastic pain and catastrophizing at a routine clinic visit (baseline). Thereafter, participants received weekly text messages that included pain interference and opioid consumption surveys. Multipredictor 2-part models were used to evaluate the predictive relationships between baseline characterizations and subsequent pain interference, and opioid consumption. RESULTS: Forty-eight AYA aged 14 to 35 completed baseline measures. Twenty-five percent of participants had scores suggestive of nociplastic pain. Greater nociplastic pain features significantly increased the odds of consuming opioids (odds ratio=1.2) and having greater interference from pain (odds ratio=1.46). Regression analyses found that greater baseline nociplastic pain characteristics were significantly associated with opioid consumption (ß=0.13) and pain interference (ß=0.061); whereas higher pain catastrophizing scores predicted less opioid consumption (ß=-0.03) and less pain interference (ß=-0.0007). DISCUSSION: In this sample of AYA with SCD, features of nociplastic pain predicted higher subsequent opioid consumption and pain interference. Being aware of nociplastic pain features in patients with SCD may better guide individualized pain management.


Assuntos
Analgésicos Opioides , Anemia Falciforme , Humanos , Adolescente , Adulto Jovem , Analgésicos Opioides/uso terapêutico , Medição da Dor , Dor/etiologia , Dor/complicações , Anemia Falciforme/complicações , Catastrofização
11.
Pediatr Blood Cancer ; 59(1): 126-32, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22180128

RESUMO

BACKGROUND: Chronic health conditions are common among long-term childhood cancer survivors, but hospitalization rates have not been reported. The objective of this study was to determine overall and cause-specific hospitalization rates among survivors of childhood cancer and compare rates to the U.S. population. PROCEDURE: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of 5+ year survivors of childhood malignancies treated at 26 participating centers. Self-reported hospitalizations from 10,366 survivors (diagnosed 1970-1986) were compared to U.S. population rates using age- and sex-stratified standardized incidence ratios (SIRs). Reasons for hospitalization were evaluated and associations between demographic, cancer and treatment-related risk factors with hospitalization were investigated. RESULTS: Survivors were, on average, 20.9 years from cancer diagnosis (SD: 4.6, range: 13-32) and 28.6 years of age (SD: 7.7, range: 13-51). Survivor hospitalization rates were 1.6 times the U.S. population (95% CI: 1.6; 1.7). Increased hospitalization rates were noted irrespective of gender, age at follow-up and cancer diagnosis, with highest SIRs noted among male (SIR = 2.6, 95% CI: 2.2; 3.0) and female (SIR = 2.7, 95% CI: 2.4; 3.1) survivors aged 45-54. Female gender, an existing chronic health condition and/or a second neoplasm, and prior treatment with radiation were associated with an increased risk of non-obstetrical hospitalization. CONCLUSIONS: Survivors of childhood cancer demonstrate substantially higher hospitalization rates. Additional research is needed to further quantify the healthcare utilization and economic impact of treatment-related complications as this population ages.


Assuntos
Hospitalização , Neoplasias/mortalidade , Sobreviventes , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/terapia , Estudos Retrospectivos , Fatores Sexuais , Fatores de Tempo , Estados Unidos/epidemiologia
12.
Account Res ; 29(5): 294-308, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-33877028

RESUMO

Variances in perceived standards regarding research integrity appear to exist between China and the U.S. An established joint institute for translational and clinical research between one Chinese and one U.S. health system provides a valuable venue in which to evaluate these perceptions better. We therefore undertook a survey of 209 physicians at the two institutions in 2013-14. The vast majority of physicians from both institutions understood the necessity of obtaining informed consent from research participants, the need to provide a description of the risks of participation, and the voluntary nature of research participation. However, there were differences in responses between the two sites in willingness to report plagiarism (U.S. 95.65% vs. Chinese 40.21%; p < .0001) and data falsification (U.S. 100% vs. Chinese 81.25%; p < .0001) and in willingness to attend biomedical industry-funded promotional events (U.S. 11.0% vs. Chinese 74.0%; p < .0001). When planning to conduct collaborative clinical research across cultures, particularly when uncertainty regarding the similarity of research cultures exists, exploration of cultural and ethical norms in research may be informative regarding educational needs and the risks of research and academic misconduct.


Assuntos
Pesquisa Biomédica , Médicos , Má Conduta Científica , China , Humanos , Plágio , Estados Unidos
13.
J Clin Oncol ; 39(20): 2266-2275, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-33630659

RESUMO

PURPOSE: To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy. METHODS: Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures. RESULTS: HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition (P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8). CONCLUSION: This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.


Assuntos
Sobreviventes de Câncer , Doença Crônica/epidemiologia , Doença de Hodgkin/terapia , Adolescente , Adulto , Idade de Início , Canadá/epidemiologia , Causas de Morte , Criança , Pré-Escolar , Doença Crônica/mortalidade , Feminino , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
14.
Blood ; 112(4): 1539-42, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18502834

RESUMO

Acute graft-versus-host disease (GVHD) remains a significant cause of mortality after hematopoietic cell transplantation (HCT). Tumor necrosis factor-alpha (TNF-alpha) mediates GVHD by amplifying donor immune responses to host tissues and by direct toxicity to target organs. We measured TNF receptor 1 (TNFR1) as a surrogate marker for TNF-alpha in 438 recipients of myeloablative HCT before transplantation and at day 7 after transplantation. Increases in TNFR1 levels more than or equal to 2.5 baseline correlated with eventual development of GVHD grade 2 to 4 (58% vs 32%, P < .001) and with treatment-related mortality (39% vs 17%, P < .001). In a multivariate analysis including age, degree of HLA match, donor type, recipient and donor sex, disease, and status at HCT, the increase in TNFR1 level at day 7 remained a significant predictor for outcome. Measurement of TNFR1 levels early after transplantation provides independent information in advance of important clinical outcomes, such as GVHD and death.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Valor Preditivo dos Testes , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Fator de Necrose Tumoral alfa/análise
15.
Pediatr Blood Cancer ; 54(2): 222-7, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19890901

RESUMO

BACKGROUND: Positron-emission tomography (PET) imaging using [(18)F]fluorodeoxyglucose (FDG) is useful for detection, staging, and monitoring a variety of malignancies, including lymphoma, in adults, but its utility in sarcomas, especially soft tissue sarcomas (STS), in children and young adults is not clear. PROCEDURE: To evaluate the potential utility of FDG PET in the care of STS in children and young adults, we analyzed 46 PET scans in 25 patients acquired over 12 years. Scans were interpreted by two imaging physicians blinded to findings from other imaging studies and clinical information. Results were compared with computed tomography and magnetic resonance imaging, biopsy results, where available, and clinical follow-up of at least 12 months. RESULTS: For a total of 46 scans in 25 patients, there were 25 true-positive scans, 3 false-positive scans, 12 true-negative scans, and 6 false-negative scans. The sensitivity of the PET scan was 86%, specificity was 80%, positive predictive value was 89%, and negative predictive value was 67%. CONCLUSION: FDG PET may be a useful imaging modality in the management of children and young adults with STS, although prospective studies are needed to establish its true utility.


Assuntos
Fluordesoxiglucose F18 , Tumores Neuroectodérmicos Primitivos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Rabdomiossarcoma/diagnóstico por imagem , Sarcoma de Ewing/diagnóstico por imagem , Adolescente , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Tumores Neuroectodérmicos Primitivos/patologia , Estudos Retrospectivos , Rabdomiossarcoma/patologia , Sarcoma de Ewing/patologia , Sensibilidade e Especificidade , Método Simples-Cego , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
Leuk Lymphoma ; 60(12): 2854-2868, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31099289

RESUMO

The availability of Erwinia Asparaginase has been limited across the world due to manufacturing shortages or for some countries due to the high acquisition cost, putting patients at risk for inferior outcomes. This manuscript provides guidance on how to manage hypersensitivity reactions and utilize therapeutic drug monitoring (TDM) to conserve and limit Erwinia use. The clinical and financial impact of a multidisciplinary committee are also discussed. Faced with a global Erwinia shortage, a multidisciplinary asparaginase allergy committee was created to review all hypersensitivity reactions to asparaginase therapy, staff education was performed on the management of asparaginase hypersensitivity reactions, an institution-wide premedication policy was mandated, and standardized guidelines were created for TDM. This multidisciplinary approach reduced the PEG-asparaginase to Erwinia switch rate from 21% (35 of 163) to 7% (10 of 134) (p = .0035). A multifaceted approach can safely maintain patients on PEG-asparaginase and conserve Erwinia for patients who need it most.


Assuntos
Antineoplásicos/provisão & distribuição , Asparaginase/provisão & distribuição , Gerenciamento Clínico , Equipes de Administração Institucional , Comunicação Interdisciplinar , Equipe de Assistência ao Paciente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/economia , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Asparaginase/economia , Tomada de Decisão Clínica , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Monitoramento de Medicamentos , Substituição de Medicamentos , Saúde Global , Guias como Assunto , Humanos
17.
Biol Blood Marrow Transplant ; 14(7): 759-65, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18541194

RESUMO

Tumor necrosis factor-alpha (TNF-alpha) is known to play a role in the pathogenesis of graft-versus-host disease (GVHD), a cause of significant morbidity and treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HCT). We measured the concentration of TNF-Receptor-1 (TNFR1) in the plasma of HCT recipients as a surrogate marker for TNF-alpha both prior to transplant and at day 7 in 82 children who underwent a myeloablative allogeneic HCT at the University of Michigan between 2000 and 2005. GVHD grade II-IV developed in 39% of patients at a median of 20 days after HCT. Increases in TNFR1 level at day 7 post-HCT, expressed as ratios compared to pretransplant baseline, correlated with the severity of GVHD (P = .02). In addition, day 7 TNFR1 ratios >2.5 baseline were associated with inferior 1-year overall survival (OS 51% versus 74%, P = .04). As an individual biomarker, TNFR1 lacks sufficient precision to be used as a predictor for the development of GVHD. However, increases in the concentration of TNFR1, which are detectable up to 2 weeks in advance of clinical manifestations of GVHD, correlate with survival in pediatric HCT patients.


Assuntos
Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Intervalo Livre de Doença , Humanos , Lactente , Condicionamento Pré-Transplante , Transplante Homólogo
18.
Pediatr Blood Cancer ; 50(4): 917-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17417790

RESUMO

Immune-mediated hemolytic anemia is a well-recognized complication of hematopoietic stem cell transplantation. We report on a 6-year-old boy with X-linked adrenoleukodystrophy who developed severe delayed alloimmune hemolytic anemia associated with immune-mediated neutropenia and thrombocytopenia following major ABO incompatible unrelated cord blood transplantation. The patient's cytopenias were refractory to treatment with corticosteroids, cyclosporine, intravenous immune globulin, rituximab, and pentostatin. After one course of Campath-1H his hematologic parameters normalized, suggesting that the compound may be an effective therapy for complex immunohematologic disorders complicating hematopoietic stem cell transplantation. The case also emphasizes the importance of T-cells in transplant associated immune cytopenias.


Assuntos
Adrenoleucodistrofia/terapia , Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Incompatibilidade de Grupos Sanguíneos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Alemtuzumab , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/fisiopatologia , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados , Criança , Sangue Fetal/transplante , Humanos , Masculino , Metilprednisolona/uso terapêutico , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Neutropenia/fisiopatologia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/fisiopatologia
19.
Acad Pediatr ; 18(4): 370-375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28606859

RESUMO

OBJECTIVE: Despite the importance of child assent, there is little consensus on what information should be disclosed and what information is most important to children for decision-making. This study was designed to compare children's/adolescents' priorities for research information with the information parents believe is most important to their children. METHODS: Child-parent dyads completed separate and independent surveys regarding information (risks, benefits, etc) that they perceived to be most important to the child to make decisions about participating in a hypothetical randomized controlled trial. Parents responded in the context of what information they believed their child (not themselves) would think important. RESULTS: Fifty-five parent-child dyads completed surveys. Although all information was deemed important, children/adolescents put greater emphasis on privacy and less on knowing the purpose of the study and the benefits compared with what their parents believed was important to their child. Adolescents (13-17 years old) placed greater importance on knowing the procedures, direct benefits, and the voluntary nature of participation compared with younger children (8-12 years old). Parents of older girls in particular placed greater emphasis on their daughter's need to know the purpose of the study, the procedures, benefits, and voluntary nature, compared with parents of boys. CONCLUSIONS: Results show that the information priorities of children/adolescents considering participation in a randomized controlled trial differ from that which their parents think is important to them. Pediatric researchers can use this knowledge to ensure that parents do not conflate their own expectations/priorities with those of their child and that children receive the information they need.


Assuntos
Tomada de Decisões , Revelação , Pais , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Criança , Feminino , Humanos , Masculino , Privacidade , Medição de Risco , Fatores Sexuais , Inquéritos e Questionários
20.
Leuk Lymphoma ; 48(4): 699-707, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17454627

RESUMO

Flurodeoxyglucose PET (FDG PET) is very useful for staging and restaging adult lymphomas. Its effectiveness in childhood lymphomas is less established. To evaluate the potential utility of FDG PET in the care of pediatric patients with lymphomas, we examined the clinical data and imaging findings of 26 patients, 8 - 19 years of age (14 HD, 12 NHL) who underwent 55 FDG PET studies. Results were compared with CT/MRI and gallium scans. FDG PET provided incremental, clinically important information in 21% of HD cases and 33% of NHL cases. It was especially useful in distinguishing scar tissue from residual disease at the end of therapy. In both HD and NHL, FDG PET had higher sensitivity (94%, 90%) and specificity (100%, 88%) than CT/MRI and gallium scanning. These results indicate that FDG PET is useful in the management of pediatric lymphomas.


Assuntos
Fluordesoxiglucose F18/farmacologia , Radioisótopos de Gálio/uso terapêutico , Doença de Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Linfoma/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Cintilografia/métodos , Adolescente , Antineoplásicos/farmacologia , Criança , Pré-Escolar , Feminino , Doença de Hodgkin/diagnóstico , Humanos , Linfoma não Hodgkin/diagnóstico , Imageamento por Ressonância Magnética/métodos , Masculino , Tomografia Computadorizada por Raios X/métodos
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