RESUMO
Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Quimioterapia de Indução , Neuroblastoma , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Neuroblastoma/genética , Masculino , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/patologia , Quimioterapia de Indução/efeitos adversos , Lactente , Fator H do Complemento/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mutação em Linhagem GerminativaRESUMO
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with diagnosis preceded by symptoms that may include fever, weight loss, fatigue, bleeding, and bruising. Timely diagnosis and treatment of ALL may lead to improved outcomes and reduced morbidity from associated complications, including tumor lysis syndrome, hyperviscosity, and stroke. We performed a retrospective cohort analysis of 274 pediatric pre-B cell ALL and acute lymphoblastic lymphoma patients within Montefiore Health System to determine whether there were factors associated with time from symptom onset to diagnosis. The median time to diagnosis for all patients was 11.5 days (interquartile range: 7.8, 14.3). Those with Medicaid insurance (n=189) were diagnosed sooner than those with private/self-pay insurance (n=85) (median of 10 vs. 16 days; P =0.05). English and other language speakers experienced fewer median days from symptom onset to diagnosis date compared with Spanish speakers (11 vs. 7 vs. 14; P =0.05). Insurance status may impact the time to diagnosis to a greater degree in non-Hispanic patients, while the English language and female sex may represent a greater advantage to Hispanic patients. Insurance status and language preference may impact the time to diagnosis of pediatric ALL. There is a further need to confirm our findings and to study possible causes driving these disparities.
Assuntos
Etnicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Estados Unidos , Criança , Humanos , Feminino , Estudos Retrospectivos , Medicaid , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Cobertura do SeguroRESUMO
Idiopathic pneumonia syndrome (IPS) is a life-threatening complication of hematopoietic cell transplantation, but it is not clearly described following chimeric antigen receptor (CAR) T-cell therapy. We describe a child who developed IPS after receiving tisagenlecleucel for post-hematopoietic cell transplantation relapsed acute lymphoblastic leukemia and had a remarkable improvement after treatment with corticosteroids and etanercept. We discuss the implications of cytokine signaling in IPS and immunologic considerations of allogeneic CAR T cells. We anticipate that the incidence of IPS and other allogeneic phenomena will be observed more often as allogeneic CAR T cells are employed in more varied settings with more mismatched donors.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Pneumonia , Receptores de Antígenos Quiméricos , Insuficiência Respiratória , Humanos , Criança , Receptores de Antígenos de Linfócitos T , Imunoterapia Adotiva/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: We report dose-escalation results from an open-label, phase 1/2 trial evaluating avelumab (anti-PD-L1) in paediatric patients with refractory/relapsed solid tumours. METHODS: In phase 1, patients aged < 18 years with solid (including central nervous system [CNS]) tumours for which standard therapy did not exist or had failed were enrolled in sequential cohorts of 3-6 patients. Patients received avelumab 10 or 20 mg/kg intravenously every 2 weeks. Primary endpoints were dose-limiting toxicities (DLTs) and grade ≥ 3 treatment-emergent adverse events (AEs). RESULTS: At data cut-off (27 July 2021), 21 patients aged 3-17 years had received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15). One patient had three events that were classified as a DLT (fatigue with hemiparesis and muscular weakness associated with pseudoprogression; 20 mg/kg cohort). Grade ≥ 3 AEs occurred in five (83%) and 11 (73%) patients in the 10 and 20 mg/kg cohorts, respectively, and were treatment-related in one patient (7%; grade 3 [DLT]) in the 20 mg/kg cohort. Avelumab exposure in paediatric patients receiving 20 mg/kg dosing, but not 10 mg/kg, was comparable or higher compared with approved adult dosing (10 mg/kg or 800 mg flat dose). No objective responses were observed. Four patients with CNS tumours (20 mg/kg cohort) achieved stable disease, which was ongoing in two patients with astrocytoma at cut-off (for 24.7 and 30.3 months). CONCLUSION: In paediatric patients with refractory/relapsed solid tumours, avelumab monotherapy showed a safety profile consistent with previous adult studies, but clinical benefits were limited.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Estudos de Coortes , Fadiga , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
BACKGROUND: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 106 /kg) (Group B2) following failed SM and first apheresis attempts. RESULTS: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.
Assuntos
Benzilaminas/uso terapêutico , Ciclamos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Células-Tronco de Sangue Periférico/efeitos dos fármacos , Adolescente , Antígenos CD34/sangue , Remoção de Componentes Sanguíneos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Linfoma/tratamento farmacológico , Linfoma/terapia , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Meduloblastoma/terapia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , Neuroblastoma/terapia , Células-Tronco de Sangue Periférico/metabolismo , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Sarcoma/terapia , Adulto JovemRESUMO
The novel coronavirus, SARS-CoV-2, causes much more severe disease in adults than in children. Although it is anticipated that immune compromised children and children with cancer may be at higher risk of developing severe or fatal COVID-19, there are no currently published reports of fatal disease in a child with cancer. Because of the discrepancy in disease severity between adult and pediatric patients, we report the case of an adolescent with pulmonary metastatic osteosarcoma who died of COVID-19 early in the course of the pandemic in New York City in the hope that heightening awareness that pulmonary metastatic disease may predispose to a more severe outcome will increase surveillance in this vulnerable population.
Assuntos
Neoplasias Ósseas/patologia , COVID-19/complicações , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Insuficiência Respiratória/patologia , SARS-CoV-2/isolamento & purificação , Neoplasias Ósseas/complicações , Neoplasias Ósseas/virologia , COVID-19/virologia , Criança , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/virologia , Masculino , Osteossarcoma/complicações , Osteossarcoma/virologia , Insuficiência Respiratória/etiologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Outcome of patients with osteosarcoma (OS) and Ewing sarcoma (EWS) is dependent on presence of metastases. Imaging guidelines for OS and EWS include radiographs, computed tomography (CT), and magnetic resonance imaging for primary tumor evaluation and CT chest and bone scintigraphy (BS) for metastatic detection. 18Fluorodeoxyglucose (18FDG) positron emission tomography (PET)/CT has become more common for disease evaluation, yet there is no consensus for its use in this population. OBJECTIVE: We aimed to compare identification of osseous metastases using BS versus 18FDG PET/CT in our patient population. We hypothesized that 18FDG PET/CT is more likely to detect osseous metastases both at diagnosis and relapse. MATERIALS AND METHODS: We performed retrospective chart reviews of pediatric sarcoma patients treated at our institution from 2008 to 2019. Paired BS and 18FDG PET/CT scans were reviewed. Review of the literature was also performed. RESULTS: Thirty-three patients had paired BS and 18FDG PET/CT during diagnosis or treatment. Fifteen patients had distant osseous metastases. In the OS cohort, 8/16 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 75% on BS. Thirty-one bony lesions were seen on imaging in OS patients; 100% of these were identified on 18FDG PET/CT but only 29% on BS. In the EWS cohort, 6/15 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 50% on BS. Eighteen bony lesions were seen on imaging in EWS patients; 94% of these were identified on 18FDG PET/CT, but only 28% on BS. CONCLUSION: For patients in our institution with OS or EWS, osseous metastases were more likely detected using 18FDG PET/CT.
Assuntos
Neoplasias Ósseas/secundário , Fluordesoxiglucose F18/metabolismo , Imageamento por Ressonância Magnética/métodos , Osteossarcoma/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Sarcoma de Ewing/patologia , Adolescente , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/metabolismo , Osteossarcoma/cirurgia , Prognóstico , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/cirurgia , Adulto JovemRESUMO
BACKGROUND: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma. PROCEDURE: Using a Simon's two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response. RESULTS: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14-27). Patients were heavily pretreated (median 3 prior regimens, range, 1-7). Thirty-five cycles were administered (median 2, range, 1-8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients. CONCLUSIONS: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Albuminas/administração & dosagem , Neoplasias Ósseas/patologia , Criança , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Prognóstico , Sarcoma de Ewing/patologia , Adulto Jovem , GencitabinaRESUMO
Wnt molecules are a class of cysteine-rich secreted glycoproteins that participate in various developmental events during embryogenesis and adult tissue homeostasis. Since its discovery in 1982, the roles of Wnt signaling have been established in various key regulatory systems in biology. Wnt signals exert pleiotropic effects, including mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway in humans has been shown to be involved in a wide variety of disorders including colon cancer, sarcoma, coronary artery disease, tetra-amelia, Mullerian duct regression, eye vascular defects, and abnormal bone mass. The canonical Wnt pathway functions by regulating the function of the transcriptional coactivator ß-catenin, whereas noncanonical pathways function independent of ß-catenin. Although the role of Wnt signaling is well established in epithelial malignancies, its role in mesenchymal tumors is more controversial. Some studies have suggested that Wnt signaling plays a pro-oncogenic role in various sarcomas by driving cell proliferation and motility; however, others have reported that Wnt signaling acts as a tumor suppressor by committing tumor cells to differentiate into a mature lineage. Wnt signaling pathway also plays an important role in regulating cancer stem cell function. In this review, we will discuss Wnt signaling pathway and its role in osteosarcoma.
Assuntos
Neoplasias Ósseas , Proteínas Wnt , Via de Sinalização Wnt , Neoplasias Ósseas/metabolismo , Diferenciação Celular , Humanos , Osteossarcoma/metabolismo , Proteínas Wnt/metabolismo , beta CateninaRESUMO
We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.
Assuntos
Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Condicionamento Pré-Transplante , Doadores não Relacionados , Proteínas WT1/sangue , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Neoplasia Residual , Transplante HomólogoRESUMO
Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.
Assuntos
Algoritmos , Medicina Baseada em Evidências/métodos , Rabdomiossarcoma/terapia , Ensaios Clínicos como Assunto , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Adolescente , Amputação Cirúrgica , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Bevacizumab/farmacocinética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/cirurgia , Criança , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Humanos , Salvamento de Membro , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Osteossarcoma/mortalidade , Osteossarcoma/cirurgia , Complicações Pós-Operatórias/induzido quimicamente , Taxa de Sobrevida , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Cicatrização/efeitos dos fármacos , Adulto JovemRESUMO
High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.
Assuntos
Transplante de Medula Óssea/métodos , Ciclofosfamida/uso terapêutico , Neoplasias/terapia , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Sobrevivência de Enxerto , Humanos , Neoplasias/mortalidade , Transplante Haploidêntico/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
Lower-intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n = 40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide from 2003 to 2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplantation immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus. Donor engraftment occurred in 29 of 32 (91%), with median time to engraftment of neutrophils >500/µL of 16 days (range, 13 to 22) and for platelets >20,000/µL without transfusion of 18 days (range, 12 to 62). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV and grades III and IV at day 100 were 33% and 5%, respectively. The cumulative incidence of chronic GVHD was 23%, with 7% moderate-to-severe chronic GVHD, according to National Institutes of Health consensus criteria. Transplantation-related mortality (TRM) at 1 year was 13%. The cumulative incidence of relapse at 2 years was 52%. With a median follow-up of 20 months (range, 3 to 148), 1-year actuarial overall and event-free survival were 56% and 43%, respectively. Thus, we demonstrate excellent rates of engraftment, GVHD, and TRM in pediatric/young adult patients treated with this regimen. This approach is a widely available, safe, and feasible option for pediatric and young adult patients with high-risk hematologic malignancies, including those with a prior history of myeloablative BMT and/or those with comorbidities or organ dysfunction that preclude eligibility for myeloablative BMT.
Assuntos
Transplante de Medula Óssea , Ciclofosfamida/uso terapêutico , Neoplasias Hematológicas/terapia , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Risco , Resultado do Tratamento , Adulto JovemRESUMO
When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review presents a concise document and figures as a starting point for evidence-based care for patients with these rare diseases. This framework allows prospective decision making and prioritization of clinical trials. It is hoped that this framework will inspire and focus future clinical research and thus lead to new trials to improve efficacy and reduce toxicity. Cancer 2017;123:2206-2218. © 2017 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/terapia , Tomada de Decisão Clínica , Recidiva Local de Neoplasia/terapia , Procedimentos Ortopédicos , Osteossarcoma/terapia , Radioterapia , Sarcoma de Ewing/terapia , Adolescente , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Equipe de Assistência ao Paciente , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Sarcoma/terapia , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Adulto JovemRESUMO
BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Cordoma/tratamento farmacológico , Dasatinibe/uso terapêutico , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Tumores Fibrosos Solitários/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Neoplasias Ósseas/mortalidade , Condrossarcoma/mortalidade , Cordoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Sarcoma Alveolar de Partes Moles/mortalidade , Tumores Fibrosos Solitários/mortalidade , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Anthracycline use is limited by cardiotoxicity, including arrhythmias and left ventricular (LV) dysfunction. We aim to characterize the association between electrophysiological changes and LV dysfunction. METHODS: A retrospective chart review was conducted, including all 147 pediatric cancer survivors at our institution over 18 years of age and treated with an anthracycline. One hundred thirty-four patients who had at least one electrocardiogram (ECG) and echocardiogram were analyzed. The association between dysfunction and baseline characteristics, treatment history, and electrocardigraphic parameters were analyzed using multivariable logistic regression. Additionally, a longitudinal generalized estimating equation (GEE) model was used to examine the temporal association between repeated measure corrected QT (QTc) intervals and subsequent LV function. RESULTS: In our population, 24% of patients had LV dysfunction. The initial posttreatment QTc interval was longer in patients with LV dysfunction (438 ± 35 vs. 420 ± 20 msec, P = 0.002). In logistic regression analysis, QTc interval (P < 0.001) and cumulative radiation dose (P = 0.027) were associated with LV dysfunction. On ECGs performed prior to evidence of LV dysfunction, the QTc was longer than on ECGs preceding a normal echocardiogram (451 ± 32 msec vs. 423 ± 25 msec, P < 0.001). Mean time from QTc ≥ 450 msec to evidence of LV dysfunction was 1.8 ± 2.9 years. In the longitudinal GEE model, QTc prolongation was associated with subsequent decreased fractional shortening. CONCLUSIONS: Among adult survivors of pediatric cancer treated with anthracyclines, prolongation of the QTc interval was associated with subsequent LV dysfunction.
Assuntos
Antraciclinas/efeitos adversos , Neoplasias/complicações , Disfunção Ventricular Esquerda/induzido quimicamente , Adulto , Criança , Eletrocardiografia , Fenômenos Eletrofisiológicos , Feminino , Seguimentos , Humanos , Masculino , Neoplasias/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , SobreviventesRESUMO
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.