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1.
Artigo em Inglês | MEDLINE | ID: mdl-35232817

RESUMO

Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in TP53 are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels.


Assuntos
Neoplasias do Córtex Suprarrenal , Neoplasias da Mama , Síndrome de Li-Fraumeni , Proteína Supressora de Tumor p53 , Adulto , Neoplasias da Mama/genética , Criança , Feminino , Duplicação Gênica/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética
2.
Laryngoscope ; 132(10): 2071-2075, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35043981

RESUMO

OBJECTIVES/HYPOTHESIS: Systemic bevacizumab is a new adjuvant therapy for recurrent respiratory papillomatosis (RRP) that has shown promising preliminary results in children. The objective of this study was to report the largest series to date that includes long-term follow-up data on bevacizumab treatment. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective review of seven pediatric patients treated within the past 6 years with systemic bevacizumab for RRP refractory to traditional debridement. RESULTS: All seven patients had a significant reduction in disease burden after initiation of systemic bevacizumab. There have been no major complications associated with systemic therapy so far. Median duration of bevacizumab treatment was 2.13 years. Three of the seven patients have been on treatment for over 3 years with the longest duration of treatment in our first patient now at 5.5 years. One patient experienced significant disease recurrence on two occasions when therapy was temporarily discontinued and was recently diagnosed with squamous cell carcinoma of the lung. CONCLUSION: Systemic bevacizumab is an effective therapy for cases of severe RRP with promising results both in short-term and long-term follow-up. Side effects are minimal. Patients must be followed closely to determine appropriate dosing intervals to control disease and to screen for disease progression. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2071-2075, 2022.


Assuntos
Infecções por Papillomavirus , Infecções Respiratórias , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Criança , Seguimentos , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Infecções por Papillomavirus/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Estudos Retrospectivos
3.
Cancer Chemother Pharmacol ; 87(6): 807-815, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33677616

RESUMO

PURPOSE: High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed. METHODS: Patients were randomized by cycle to 4 h or 12 h HDMTX (12 g/m2) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFRCr or GFRcysC) were obtained. Serum and urine methotrexate concentrations [MTX] were measured. RESULTS: Patients (n = 12), median (range) age 12.4 (5.7-19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine [MTX] were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4) mM at the end of 4 h infusion and 557 (493, 586) µM and 11.1 (9.9, 21.1) mM at the end of 12 h infusion. Time to serum [MTX] < 0.1 µM was 83 (80.7, 90.7) h and 87 (82.8, 92.4) h for 4 and 12 h infusions. GFRCr was highly variable, increased after cisplatin, and exceeded 150 ml/min/1.73 m2. GFRcysC was less variable and decreased at the end of therapy. AKI biomarkers were elevated indicating acute tubular dysfunction, however, did not differ between 4 and 12 h infusions. Radiographic and histological response were similar for patients receiving 4 h or 12 h infusions; the median percent tumor necrosis was > 95%. CONCLUSIONS: Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFRcysC was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity. CLINICAL TRIAL: NCT01848457.


Assuntos
Abortivos não Esteroides/administração & dosagem , Abortivos não Esteroides/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Biomarcadores/metabolismo , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Osteossarcoma/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Osteossarcoma/metabolismo , Adulto Jovem
4.
J Pediatr Hematol Oncol ; 42(5): e305-e309, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32079986

RESUMO

BACKGROUND: The use of radiation therapy to treat metastases in patients with metastatic Ewing sarcoma (MES) has been controversial and variable. The authors report outcomes and patterns of failure after metastatic site irradiation (MSI). PROCEDURE: A total of 27 pediatric patients with MES were treated with chemotherapy and received radiation therapy to their primary site. Ten patients additionally received MSI, which consisted of whole-lung irradiation (WLI) in patients with lung metastases. Metastatic sites were followed from diagnosis to the first relapse. RESULTS: Median follow-up was 29 months. Seventy-eight percent of patients relapsed. Two-year progression-free survival (PFS) and overall survival with and without MSI were 30 versus 29% (log rank P=0.38) and 60 versus 70% (log rank P=0.11), respectively. The median time to relapse among patients who relapsed was 19.5 versus 12.3 months for those receiving MSI versus those who did not (P=0.04).Seven of 20 (35%) patients with lung metastases received WLI±other MSI. Two-year PFS with and without MSI was 43% versus 23% (log rank P=0.02). Among patients with a complete response to computed tomography, 5 of 14 (36%) patients received MSI. Two-year PFS with and without MSI was 60% versus 33% (log rank P=0.04).In the cohort of patients who relapsed, among all metastatic sites at diagnosis, the disease recurred at 15% of irradiated sites and 31% of unirradiated sites. On logistic regression, no factors were statistically associated with increased risk of recurrence at initial sites of metastases. CONCLUSIONS: Relapses frequently occur at sites of prior unirradiated disease in patients with MES. WLI may improve 2-year PFS, regardless of chemotherapy response. Further investigation of the role of MSI is warranted.


Assuntos
Neoplasias Ósseas/mortalidade , Neoplasias Pulmonares/mortalidade , Radioterapia/mortalidade , Sarcoma de Ewing/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Adolescente , Adulto , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Masculino , Prognóstico , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Sarcoma de Ewing/radioterapia , Neoplasias de Tecidos Moles/radioterapia , Neoplasias de Tecidos Moles/secundário , Taxa de Sobrevida , Adulto Jovem
5.
Int J Radiat Oncol Biol Phys ; 104(2): 401-408, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30738983

RESUMO

PURPOSE: Patients with high-risk neuroblastoma (HR-NBL) require radiation to the primary tumor site and sites of persistent metastatic disease. Proton radiation therapy (PRT) may promote organ sparing, but long-term outcomes have not been studied. METHODS AND MATERIALS: Sequential patients with HR-NBL received PRT: 2160 cGy (relative biological effectiveness) to primary tumor bed and persistent metastatic sites, with 3600 cGy (relative biological effectiveness) to gross residual disease. RESULTS: From September 2010 through September 2015, 45 patients with HR-NBL received PRT after systemic therapy, primary tumor resection, and high-dose chemotherapy with stem cell rescue. Median age was 46 months at the time of PRT (range, 10 months to 12 years); 23 patients (51%) were male. Primary tumors were adrenal in 40 (89%); 11 (24%) received boost. Ten metastatic sites in 8 patients were radiated. Double scattered proton beams were used for 19 (42%) patients, in combination with x-rays for 2 (5%). The remaining 26 (58%) received pencil beam scanning, available since January 2013. We observed 97% freedom from primary site recurrence at 3, 4, and 5 years. Overall survival rates were 89%, 80%, and 80% and disease-free survival rates were 77%, 70%, and 70%, at 3, 4, and 5 years, respectively. With median follow-up of 48.7 months from diagnosis (range, 11-90 months) for all patients (57.4 months for those alive), 37 (82%) patients are alive, and 32 (71%) are without evidence of disease. One patient experienced locoregional recurrence; the remaining 12 (27%) experienced relapse at distant, nonradiated sites. Acute toxicities during treatment were mainly grade 1. No patient has experienced World Health Organization grade 3 or 4 long-term renal or hepatic toxicity. Pencil beam scanning plans required less planning time and resources than double scattered plans. CONCLUSIONS: We observe excellent outcomes in patients treated with PRT for HR-NBL from 2010 through 2015, with 82% of patients alive and 97% free of primary site recurrence. No patient has experienced long-term renal or liver toxicity. This treatment maximizes normal tissue preservation and is appropriate for this patient population.


Assuntos
Neuroblastoma/radioterapia , Terapia com Prótons/métodos , Neoplasias das Glândulas Suprarrenais/radioterapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neoplasia Residual , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/secundário , Terapia com Prótons/efeitos adversos , Eficiência Biológica Relativa , Risco , Taxa de Sobrevida , Neoplasias Torácicas/radioterapia , Neoplasias Torácicas/secundário , Fatores de Tempo , Resultado do Tratamento
6.
Pediatr Blood Cancer ; 65(10): e27296, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29932284

RESUMO

Beckwith-Wiedemann syndrome (BWS) is a genetic syndrome associated with overgrowth and cancer predisposition, including predisposition to Wilms tumor (WT). Patients with BWS and BWS spectrum are screened from birth to age 7 years for BWS-associated cancers. However, in some cases a BWS-associated cancer may be the first recognized manifestation of the syndrome. We describe 12 patients diagnosed with BWS after presenting with a WT. We discuss the features of BWS in these patients and hypothesize that earlier detection of BWS by attention to its subtler manifestations could lead to earlier detection of children at risk for associated malignancies.


Assuntos
Síndrome de Beckwith-Wiedemann/complicações , Síndrome de Beckwith-Wiedemann/diagnóstico , Neoplasias Renais/genética , Tumor de Wilms/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
7.
Oncologist ; 23(7): 762-e79, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29445029

RESUMO

LESSONS LEARNED: Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short-term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin-associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient-reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring "at least rarely" after cycle 1, prior to objective high-frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long-term toxicity are needed. BACKGROUND: Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole. MATERIALS AND METHODS: Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6-19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle. RESULTS: Pantoprazole had no impact on decrements in hearing threshold at 4-8 kHz, post-treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died. CONCLUSION: Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N-acetyl-ß-glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Cisplatino/efeitos adversos , Audição/efeitos dos fármacos , Rim/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Pantoprazol/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Estudos Cross-Over , Doxorrubicina/administração & dosagem , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/tratamento farmacológico , Humanos , Masculino , Metotrexato/administração & dosagem , Transportador 2 de Cátion Orgânico/uso terapêutico , Osteossarcoma/patologia , Adulto Jovem
8.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28834048

RESUMO

Vincristine (VCR) is a vinca alkaloid and common chemotherapeutic that is used to treat multiple pediatric and adult malignancies. Despite its common use, cases of anaphylaxis to VCR are rare and typically isolated to a single individual. We report a series of eight patients with adverse reactions to VCR over the course of 11 months at a single institution, four of which progressed to anaphylaxis and one of which resulted in cardiac arrest. Mass spectrometry analysis of medication lots was performed to test for possible contaminant(s). Our findings highlight the risk of anaphylaxis during therapy with VCR.


Assuntos
Anafilaxia , Contaminação de Medicamentos , Neoplasias/tratamento farmacológico , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adolescente , Anafilaxia/induzido quimicamente , Anafilaxia/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Espectrometria de Massas , Fatores de Risco , Vincristina/análise
9.
Pediatr Blood Cancer ; 65(4)2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29286549

RESUMO

Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.


Assuntos
Neoplasias Ósseas/patologia , Transtornos do Crescimento , Transplante de Células-Tronco Hematopoéticas , Neoplasias Induzidas por Radiação/patologia , Osteonecrose , Irradiação Corporal Total/efeitos adversos , Feminino , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/patologia , Humanos , Masculino , Osteonecrose/etiologia , Osteonecrose/patologia , Escorregamento das Epífises Proximais do Fêmur/etiologia , Escorregamento das Epífises Proximais do Fêmur/patologia
10.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29058370

RESUMO

PURPOSE: Pediatric head and neck malignancies are managed with intensive multimodality therapy. Proton beam therapy (PBT) may reduce toxicity by limiting exposure of normal tissue to radiation. In this study, we report acute toxicities and early outcomes following PBT for pediatric head and neck malignancies. MATERIALS AND METHODS: Between 2010 and 2016, pediatric patients with nonhematologic malignancies of the head and neck were treated with PBT. Clinical and dosimetric data were abstracted from the medical record and treatment planning system with institutional review board approval. RESULTS: Sixty-nine consecutive pediatric patients were treated with proton-based radiotherapy for head and neck malignancies. Thirty-five were treated for rhabdomyosarcoma to a median dose of 50.4 Gy relative biological effectiveness [RBE]. Ten patients were treated for Ewing sarcoma to a median dose of 55.8 Gy[RBE]. Twenty-four patients were treated for other histologies to a median dose of 63.0 Gy[RBE]. Grade 3 oral mucositis, anorexia, and dysphagia were reported to be 4, 22, and 7%, respectively. Actuarial 1-year freedom from local recurrence was 92% (95% CI 80-97). Actuarial 1-year overall survival was 93% (95% CI 79-98) in the entire cohort. Oral cavity mucositis was significantly correlated with oral cavity dose (D80 and D50 [P < 0.05], where D80 and D50 are dose to 50% of the volume and dose to 80% of the volume, respectively). CONCLUSIONS: In this study, we report low rates of acute toxicity in a cohort of pediatric patients with head and neck malignancies. PBT appears safe for this patient population, with local control rates similar to historical reports. Longer follow-up will be required to evaluate late toxicity and long-term disease control.


Assuntos
Neoplasias de Cabeça e Pescoço , Terapia com Prótons , Rabdomiossarcoma , Sarcoma de Ewing , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Lactente , Masculino , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/radioterapia , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/radioterapia , Taxa de Sobrevida
12.
J Pediatr Hematol Oncol ; 40(4): e239-e242, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29240034

RESUMO

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by aggressive local invasion and a syndrome of platelet trapping known as Kasabach-Merritt phenomenon that, through deposition of platelet derived growth factors, may perpetuate the growth of the tumor. Although many cases of KHE are successfully treated with local control or low-intensity chemotherapy, some cases are often refractory even to aggressive treatment. Herein, we describe a patient with a refractory, recurrent KHE despite multiple attempts at local control and intensive chemotherapy, that ultimately was successfully treated with rationally designed and low-intensity combination therapy of sirolimus and aspirin.


Assuntos
Aspirina/administração & dosagem , Hemangioendotelioma , Síndrome de Kasabach-Merritt , Sarcoma de Kaposi , Sirolimo/administração & dosagem , Criança , Hemangioendotelioma/tratamento farmacológico , Hemangioendotelioma/patologia , Humanos , Síndrome de Kasabach-Merritt/tratamento farmacológico , Síndrome de Kasabach-Merritt/patologia , Masculino , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/patologia
14.
J Pediatr Hematol Oncol ; 36(3): e202-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24072248

RESUMO

Ectopic production of ß-human chorionic gonadotropin (ß-hCG) by nontrophoblastic tumors has been reported but mostly in carcinomas. We report a case of an adolescent female patient with a epithelioid osteosarcoma that was discovered to secrete ß-hCG after routine pregnancy testing. Immunohistochemical staining of her primary tumor biopsy demonstrated immunoreactivity for ß-hCG. Levels of serum ß-hCG were monitored throughout her therapy and demonstrated normalization with effective systemic therapy and local control. She remains disease free 6 months off therapy, with undetectable hormone levels. A review of the available literature on ß-hCG production by sarcomas is also presented.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/metabolismo , Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Osteossarcoma/metabolismo , Sarcoma/metabolismo , Adolescente , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Gravidez , Testes de Gravidez , Prognóstico , Sarcoma/tratamento farmacológico , Sarcoma/patologia
15.
Pediatr Blood Cancer ; 60(10): 1606-11, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23737005

RESUMO

BACKGROUND: Proton therapy for treatment for high-risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity-modulated X-ray therapy (IMXT). PROCEDURE: Double-scattered proton plans and IMXT plans delivering 2,160 cGy to the primary tumor site and other residual disease were developed for 13 consecutive HR-NBL patients. Radiation doses to target volumes and OAR were calculated to determine the optimal modality for each. RESULTS: All patients received radiation (5/13 ≥ 2 sites). No patient has experienced local recurrence or clinical organ toxicity. Coverage was excellent using both protons and IMXT: median % dose delivered to 95% clinical target volume was 99% and 100%, respectively. For nine patients with lateralized disease, proton therapy offered sparing of the contralateral kidney both with regard to median dose and dose to 20% (median <1 cGy vs. 362 cGy, P = 0.01; median 100 cGy vs. 634 cGy, P = 0.02, respectively). Proton therapy did not reduce ipsilateral kidney dose, and for 2 select patients with lateralized disease IMXT improved overall bilateral renal sparing. Proton therapy improved median bowel (median 33 cGy vs. 590 cGy, P = 0.01), total body (median <1 cGy vs. 30 cGy, P = 0.15), and liver dose (median <1 cGy vs. 529, P < 0.001). When chest RT was required, proton therapy decreased median heart dose and mean lung dose. CONCLUSIONS: For most patients (11/13), proton therapy offered the optimal combination of target coverage and organ sparing, and is a feasible treatment for HR-NBL. We recommend a customized approach with careful evaluation of renal dosimetry; IMXT may be preferred for select patients.


Assuntos
Neuroblastoma/radioterapia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Terapia com Prótons/métodos , Dosagem Radioterapêutica , Terapia por Raios X/métodos
17.
Cancer Res ; 70(7): 2749-58, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20233875

RESUMO

Cancer genomic studies that rely on analysis of biopsies from primary tumors may not fully identify the molecular events associated with tumor progression. We hypothesized that characterizing the transcriptome during tumor progression in the TH-MYCN transgenic model would identify oncogenic drivers that would be targetable therapeutically. We quantified expression of 32,381 murine genes in nine hyperplastic ganglia harvested at three time points and four tumor cohorts of progressively larger size in mice homozygous for the TH-MYCN transgene. We found 93 genes that showed a linearly increasing or decreasing pattern of expression from the preneoplastic ganglia to end stage tumors. Cross-species integration identified 24 genes that were highly expressed in human MYCN-amplified neuroblastomas. The genes prioritized were not exclusively driven by increasing Myc transactivation or proliferative rate. We prioritized three targets [centromere-associated protein E (Cenpe), Gpr49, and inosine monophosphate dehydrogenase type II] with previously determined roles in cancer. Using siRNA knockdown in human neuroblastoma cell lines, we further prioritized CENPE due to inhibition of cellular proliferation. Targeting CENPE with the small molecular inhibitor GSK923295 showed inhibition of in vitro proliferation of 19 neuroblastoma cell lines (median IC(50), 41 nmol/L; range, 27-266 nmol/L) and delayed tumor growth in three xenograft models (P values ranged from P < 0.0001 to P = 0.018). We provide preclinical validation that serial transcriptome analysis of a transgenic mouse model followed by cross-species integration is a useful method to identify therapeutic targets and identify CENPE as a novel therapeutic candidate in neuroblastoma.


Assuntos
Proteínas Cromossômicas não Histona/genética , Neuroblastoma/genética , Algoritmos , Animais , Processos de Crescimento Celular/genética , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Progressão da Doença , Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Ativação Transcricional
18.
Clin Cancer Res ; 16(5): 1478-85, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20179224

RESUMO

PURPOSE: Neuroblastoma, a common pediatric tumor of the sympathetic nervous system, is characterized by clinical heterogeneity. The Trk family neurotrophin receptors play an important role in this behavior. Expression of TrkA is associated with favorable clinical features and outcome, whereas TrkB expression is associated with an unfavorable prognosis. We wanted to determine if the Trk-selective inhibitor lestaurtinib had therapeutic efficacy in a preclinical neuroblastoma model. EXPERIMENTAL DESIGN: We performed intervention trials of lestaurtinib alone or in combination with other agents in TrkB-overexpressing neuroblastoma xenograft models. RESULTS: Lestaurtinib alone significantly inhibited tumor growth compared to vehicle-treated animals [P = 0.0004 for tumor size and P = 0.011 for event-free survival (EFS)]. Lestaurtinib also enhanced the antitumor efficacy of the combinations of topotecan plus cyclophosphamide (P < 0.0001 for size and P < 0.0001 for EFS) or irinotecan plus temozolomide (P = 0.011 for size and P = 0.012 for EFS). There was no additive benefit of combining either 13-cis-retinoic acid or fenretinide with lestaurtinib compared to lestaurtinib alone. There was dramatic growth inhibition combining lestaurtinib with bevacizumab (P < 0.0001), but this combination had substantial systemic toxicity. CONCLUSIONS: We show that lestaurtinib can inhibit the growth of neuroblastoma both in vitro and in vivo and can substantially enhance the efficacy of conventional chemotherapy, presumably by inhibition of the Trk/brain-derived neurotrophic factor autocrine survival pathway. It may also enhance the efficacy of selected biological agents, but further testing is required to rule out unanticipated toxicities. Our data support the incorporation of Trk inhibitors, such as lestaurtinib, in clinical trials of neuroblastoma or other tumors relying on Trk signaling pathways for survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis/uso terapêutico , Neuroblastoma/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Ativação Enzimática/efeitos dos fármacos , Furanos , Humanos , Irinotecano , Camundongos , Camundongos Nus , Receptor trkB/efeitos dos fármacos , Receptor trkB/metabolismo , Temozolomida , Topotecan/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Lancet Oncol ; 11(2): 184-92, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20152770

RESUMO

Progress in the treatment of Ewing's sarcoma, the second most common bone tumour in children and adolescents, has improved survival from about 10% in the period before chemotherapy was introduced to about 75% today for patients with localised tumours. However, patients with metastases still fare badly, and the therapy carries short-term and long-term toxicities. Multidisciplinary care is indispensable for these patients. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewing's sarcoma. Cooperative group studies have led to chemotherapy regimens using the same drugs (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), although the exact regimens differ in Europe and North America. The EWS-ETS family of gene fusions and their downstream effects in Ewing's sarcomas provide opportunities for new approaches to treatment. These include the inhibition of the fusion gene or its protein product, and pathways related to IGF1 and mTOR. Inhibition of tyrosine kinases, exploitation of non-apoptotic cell death, and interference with angiogenesis are promising new approaches. With many new approaches and relatively few patients, it will be challenging to integrate new and established treatments through clinical trials.


Assuntos
Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Antineoplásicos/uso terapêutico , Criança , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Sarcoma de Ewing/secundário , Sarcoma de Ewing/terapia
20.
J Pediatr Hematol Oncol ; 29(8): 569-73, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17762500

RESUMO

Hemophagocytic lymphohistiocytosis is a rare, life-threatening complication of Epstein Barr virus (EBV) infection. Current treatments are directed at reducing virus-induced immune dysregulation. Addition of agents that eliminate EBV-infected B cells may improve therapeutic efficacy. On the basis of the observations that the anti-CD-20 monoclonal antibody rituximab reduces disease burden in individuals with EBV-associated lymphoproliferative disorders, we treated a patient with severe EBV-hemophagocytic lymphohistiocytosis using a combination of rituximab and chemotherapy. This patient demonstrated a rapid clinical response and an 18-fold reduction in EBV viral load within 24 hours of receiving rituximab. He remains free of disease 8 months after completing treatment.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Adolescente , Anticorpos Monoclonais Murinos , Terapia Combinada , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/complicações , Humanos , Terapia de Imunossupressão , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Rituximab
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