RESUMEN
Acute onset upper extremity edema can pose a diagnostic challenge for the emergency physician, with conditions ranging from mild local allergic reactions to deep venous thrombosis to underlying life threatening conditions. We discuss a case of a 10-year-old female with upper extremity edema and the diagnostic considerations, which ultimately led to uncovering a malignant etiology. This case represents a rare presentation of her underlying diagnosis, anaplastic large cell lymphoma.
Asunto(s)
Edema/etiología , Linfoma Anaplásico de Células Grandes/complicaciones , Neoplasias/complicaciones , Extremidad Superior/patología , Enfermedad Aguda , Antineoplásicos/uso terapéutico , Niño , Servicios Médicos de Urgencia , Femenino , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Resultado del Tratamiento , Extremidad Superior/diagnóstico por imagenRESUMEN
Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rank P = .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Síndrome de Down/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Análisis Citogenético , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Síndrome de Down/genética , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/genética , Masculino , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Resultado del TratamientoRESUMEN
Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.
Asunto(s)
Pruebas Genéticas/métodos , Síndrome de Li-Fraumeni/diagnóstico , Proteína p53 Supresora de Tumor/análisis , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias Encefálicas/genética , Neoplasias de la Mama/genética , Femenino , Genes p53 , Estudios de Asociación Genética/métodos , Mutación de Línea Germinal , Humanos , Síndrome de Li-Fraumeni/genética , Linaje , Sarcoma/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
As with most genetic cancer predisposition syndromes, inherited susceptibility to myelodysplastic syndrome (MDS) and acute leukemia (AL) is likely to be more common than previously appreciated. As next-generation sequencing technologies become integrated into clinical practice, we anticipate that the number of cases of familial MDS/AL identified will increase. Although the existence of syndromes predisposing to MDS/AL has been known for some time, clinical guidelines for the screening and management of suspected or confirmed cases do not exist. Based on our collective experience caring for families with these syndromes, we propose recommendations for genetic counseling, testing, and clinical management. We welcome discussion about these proposals and hope that they will catalyze an ongoing dialog leading to optimal medical and psychosocial care for these patients.
Asunto(s)
Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Susceptibilidad a Enfermedades , Familia , Asesoramiento Genético , Pruebas Genéticas , Humanos , Leucemia/diagnóstico , Leucemia/genética , Síndromes Mielodisplásicos/genética , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891). METHODS: COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41). RESULTS: The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/µL (range, 900-164,900/µL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0-4 years [median, 1.7 years; n = 126]; P = .001). CONCLUSIONS: The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Síndrome de Down/complicaciones , Leucemia Mieloide/tratamiento farmacológico , Adolescente , Trasplante de Médula Ósea , Niño , Preescolar , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia Mieloide/complicaciones , Leucemia Mieloide/cirugía , Masculino , Tioguanina/administración & dosificación , Resultado del TratamientoRESUMEN
Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.
Asunto(s)
Citarabina/uso terapéutico , Síndrome de Down/complicaciones , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Enfermedad Aguda , Antimetabolitos Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia Megacarioblástica Aguda/complicaciones , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Mieloide/diagnóstico , Masculino , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/diagnóstico , Pronóstico , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tioguanina/administración & dosificación , Tioguanina/efectos adversos , Niño , Preescolar , Femenino , Humanos , Hipertensión Portal/inducido químicamente , Lactante , Inyecciones Espinales , Masculino , Metotrexato/administración & dosificaciónAsunto(s)
Síndrome de Down/genética , Janus Quinasa 2/genética , Janus Quinasa 3/genética , Leucemia Mieloide/genética , Mutación , Trastornos Mieloproliferativos/genética , Receptores de Trombopoyetina/genética , Niño , Preescolar , Síndrome de Down/complicaciones , Epigénesis Genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Leucemia Mieloide/etiología , Masculino , Trastornos Mieloproliferativos/etiologíaRESUMEN
We describe the successful treatment of a 5-year-old girl with rapidly evolving left hemispheric hemorrhagic infarcts resulting from left transverse and sigmoid sinus thrombosis using combined endovascular dural sinus angioplasty and local low-dose thrombolytic therapy.
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Angioplastia , Infarto Cerebral/etiología , Fibrinolíticos/uso terapéutico , Trombosis de los Senos Intracraneales/terapia , Angiografía Cerebral , Infarto Cerebral/fisiopatología , Infarto Cerebral/terapia , Preescolar , Femenino , Humanos , Trombosis de los Senos Intracraneales/complicaciones , Trombosis de los Senos Intracraneales/fisiopatologíaRESUMEN
The Children's Cancer Group (CCG) 1952 clinical trial for children with standard-risk acute lymphoblastic leukemia (SR-ALL) compared intrathecal (IT) methotrexate (MTX) with IT triples (ITT) (MTX, cytarabine, and hydrocortisone sodium succinate [HSS]) as presymptomatic central nervous system (CNS) treatment. Following remission induction, 1018 patients were randomized to receive IT MTX and 1009 ITT. Multivariate analysis identified male sex, hepatomegaly, CNS-2 status, and age younger than 2 or older than 6 years as significant predictors of isolated CNS (iCNS) relapse. The 6-year cumulative incidence estimates of iCNS relapse are 3.4% +/- 1.0% for ITT and 5.9% +/- 1.2% for IT MTX; P = .004. Significantly more relapses occurred in bone marrow (BM) and testicles with ITT than IT MTX, particularly among patients with T-cell phenotype or day 14 BM aspirate containing 5% to 25% blasts. Thus, the estimated 6-year event-free survivals (EFS) with ITT or IT MTX are equivalent at 80.7% +/- 1.9% and 82.5% +/- 1.8%, respectively (P = .3). Because the salvage rate after BM relapse is inferior to that after CNS relapse, the 6-year overall survival (OS) for ITT is 90.3% +/- 1.5% versus 94.4% +/- 1.1% for IT MTX (P = .01). It appears that ITT improves presymptomatic CNS treatment but does not improve overall outcome.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Factores de Edad , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias de la Médula Ósea/secundario , Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/mortalidad , Niño , Preescolar , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Hidrocortisona/administración & dosificación , Hidrocortisona/análogos & derivados , Inyecciones Espinales , Masculino , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Linfocitos T/patología , Neoplasias Testiculares/secundario , Factores de TiempoRESUMEN
This case represents an example of an unusual T-cell lymphoblastic leukemia/lymphoma syndrome associated with eosinophilia and myeloid malignancy in a young boy. This case is one of only five reported "leukemic" variants of the disease and demonstrates the importance of considering this poor prognostic diagnosis in pediatric acute lymphoblastic leukemia. This case also illustrates the importance of an interactive multidisciplinary approach to the laboratory evaluation of a leukemia patient.