Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 262
Filtrar
1.
Handb Exp Pharmacol ; 2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39177748

RESUMO

The outcome for children with cancer has improved significantly over the past 60 years, with more than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States and Europe, with significant short- and long-term toxicity of treatment continuing to impact most children. While the past 15 years have witnessed dramatic scientific innovation for certain cancers in adult patients, pediatric cancer treatment innovation lags increasingly behind. To help bridge the adult-pediatric therapeutic development gap, collaborative efforts are essential among stakeholders within and outside the pediatric oncology community. Prioritizing collaboration in areas such as cancer characterization, target identification and validation, drug discovery, and approaches to currently "undruggable" targets is imperative to improving the outcomes for children with cancer.

2.
Facial Plast Surg ; 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38490242

RESUMO

Otoplasty is commonly used to treat prominauris. Cartilage-sparing techniques for otoplasty are well popularized. The most common cartilage-sparing otoplasty techniques include the Mustardé and Furnas techniques. This article discusses the preparation, surgical steps, postoperative care, and associated complications for Mustardé and Furnas otoplasty in detail.

3.
Clin Pharmacol Ther ; 115(1): 36-41, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37885401

RESUMO

Better therapies for childhood cancer remain an unmet need to improve the dismal prognosis of certain malignancies and to reduce the burden of toxicity. Rescuing discontinued or shelved drugs for children, adolescents, and young adults is a strategy to identify new uses for approved or investigational medicines outside the scope of their original medical indication. Our proposed multistakeholder consensus focuses on the development of innovative, patent-protected targeted agents, sourced from previously shelved or discontinued programs that have the potential to provide significant benefit to underserved patient populations, with unmet medical needs. There are several challenges to continuing/rescuing drugs for pediatric oncology development, which include the lack of information for decision making, corporate strategy considerations underlying the decision to invest in pediatric development, and the contracting and technology transfer complexities required to enable divestment and subsequent development. The multistakeholder approach for drug development has the advantage of conveying a consensus among academia, patient advocates, and importantly industry itself. We propose three areas of action to facilitate rescuing potentially beneficial drugs for children and adolescents with cancer: (i) initiatives to provide information to companies considering developing these drugs and a standards framework; (ii) incentives both in Europe and in the United States to encourage companies to develop pediatric-only drugs, with the reform of the EU Pharmaceutical Legislation posing an important opportunity; and (iii) communication of the issues to all stakeholders. Ultimately, this will benefit children and adolescents with cancer.


Assuntos
Antineoplásicos , Neoplasias , Adolescente , Criança , Estados Unidos , Humanos , Consenso , Neoplasias/tratamento farmacológico , Oncologia , Antineoplásicos/efeitos adversos , Desenvolvimento de Medicamentos
4.
Lancet Haematol ; 9(9): e678-e688, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35870472

RESUMO

BACKGROUND: Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia. METHODS: For this retrospective cohort study from the Children's Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Children's Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Children's Hospital of Philadelphia (Philadelphia, PA, USA) from Jan 1, 2011, to Dec 31, 2014, and at the Texas Children's Hospital (Houston, TX, USA) from Jan 1, 2011, to Dec 31, 2014. The ExtractEHR automated package acquired, cleaned, and graded laboratory data as per Common Terminology Criteria for Adverse Events (CTCAE) version 5 for 22 commonly evaluated grade 3-4 adverse events (fatal events were not evaluated) with numerically based CTCAE definitions. Descriptive statistics tabulated adverse event frequencies. Adverse events ascertained by ExtractEHR were compared to manually reported adverse events for patients enrolled in two COG trials (AAML1031, NCT01371981; AALL0932, NCT02883049). Analyses were restricted to protocol-defined chemotherapy courses (induction I, induction II, intensification I, intensification II, and intensification III for acute myeloid leukaemia; induction, consolidation, interim maintenance, delayed intensification, and maintenance for acute lymphoblastic leukaemia). FINDINGS: Laboratory adverse event data from 1077 patients (583 from Children's Healthcare of Atlanta, 200 from the Children's Hospital of Philadelphia, and 294 from the Texas Children's Hospital) who underwent 4611 courses (549 for acute myeloid leukaemia and 4062 for acute lymphoblastic leukaemia) were extracted, processed, and graded. Of the 166 patients with acute myeloid leukaemia, 86 (52%) were female, 80 (48%) were male, 96 (58%) were White, and 132 (80%) were non-Hispanic. Of the 911 patients with acute lymphoblastic leukaemia, 406 (45%) were female, 505 (55%) were male, 596 (65%) were White, and 641 (70%) were non-Hispanic. Patients with acute myeloid leukaemia had the most adverse events during induction I and intensification II. Hypokalaemia (one [17%] of six to 75 [48%] of 156 courses) and alanine aminotransferase (ALT) increased (13 [10%] of 134 to 27 [17%] of 156 courses) were the most prevalent non-haematological adverse events in patients with acute myeloid leukaemia, as identified by ExtractEHR. Patients with acute lymphoblastic leukaemia had the greatest number of adverse events during induction and maintenance (eight adverse events with prevalence ≥10%; induction and maintenance: anaemia, platelet count decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, ALT increased, and hypocalcaemia; induction: hypokalaemia; maintenance: aspartate aminotransferase [AST] increased and blood bilirubin increased), as identified by ExtractEHR. 187 (85%) of 220 total comparisons in 22 adverse events in four AAML1031 and six AALL0923 courses were substantially higher with ExtractEHR than COG-reported adverse event rates for adverse events with a prevalence of at least 2%. INTERPRETATION: ExtractEHR is scalable and accurately defines laboratory adverse event rates for paediatric acute leukaemia; moreover, ExtractEHR seems to detect higher rates of laboratory adverse events than those reported in COG trials. These rates can be used for comparisons between therapies and to counsel patients treated on or off trials about the risks of chemotherapy. ExtractEHR-based adverse event ascertainment can improve reporting of laboratory adverse events in clinical trials. FUNDING: US National Institutes of Health, St Baldrick's Foundation, and Alex's Lemonade Stand Foundation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Registros Eletrônicos de Saúde , Feminino , Humanos , Hipopotassemia/epidemiologia , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos , Adulto Jovem
6.
Nat Med ; 28(5): 1014-1021, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35379979

RESUMO

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.


Assuntos
Amaurose Congênita de Leber , Adulto , Antígenos de Neoplasias/genética , Cegueira/genética , Proteínas de Ciclo Celular/genética , Criança , Proteínas do Citoesqueleto/metabolismo , Humanos , Amaurose Congênita de Leber/tratamento farmacológico , Amaurose Congênita de Leber/genética , Oligonucleotídeos Antissenso/efeitos adversos , Visão Ocular
7.
Eur J Cancer ; 166: 145-164, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35290915

RESUMO

Rapid evaluation and subsequent regulatory approval of new drugs are critical to improving survival and reducing long-term side-effects for children and adolescents with cancer. The international multi-stakeholder organisation ACCELERATE was created to advance the timely investigation of new anti-cancer drugs. ACCELERATE has enhanced communication and understanding between academia, industry, patient advocates and regulators. It has promoted a mechanism-of-action driven drug development approach and developed Paediatric Strategy Forums. These initiatives have facilitated prioritisation of medicinal products and a focused and sequential strategy for drug development where there are multiple potential agents. ACCELERATE has championed the early assessment of promising drugs in adolescents through their inclusion in adult early phase trials. ACCELERATE has strongly supported alignment between the European Medicines Agency and the US Food and Drug Administration and identification of unmet medical needs through multi-stakeholder collaboration. Early engagement between all stakeholders in the development of new drugs is critical. Innovative clinical trial designs are required, necessitating early discussion with sponsors and regulators. Amplifying the patient advocate voice through inclusion across the drug development continuum will lead to better, patient-centric trials. By these means, children and adolescents with cancer can maximally and rapidly benefit from innovative products to improve outcomes and reduce burdensome sequelae.


Assuntos
Antineoplásicos , Neoplasias , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Criança , Desenvolvimento de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration
8.
Neuro Oncol ; 24(4): 655-664, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34347089

RESUMO

BACKGROUND: A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials. METHODS: Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles. RESULTS: Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled in the phase II study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (P = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89-13.1%) and 1-year OS was 39.2% (27.8-50.5%). CONCLUSIONS: Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly diagnosed DIPG but failed to improve outcome.


Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Astrocitoma/tratamento farmacológico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/radioterapia , Criança , Glioma Pontino Intrínseco Difuso/terapia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Vorinostat
9.
J Clin Oncol ; 39(33): 3716-3724, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34570655

RESUMO

PURPOSE: A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents. PATIENTS AND METHODS: We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R. The primary end point was event-free survival (EFS). Overall survival and toxicity were also assessed. This trial was registered (ClinicalTrials.gov identifier: NCT01516567). RESULTS: Analyses were based on 46 patients. The median age was 15.4 years (interquartile range: 14-16 years). The median follow-up was 59.0 months (interquartile range: 52.6-69.2 months). Fourteen events were observed (eight relapses or progressions (including three parenchymal CNS relapses), four residual lymphoma, and two second malignancies). The 4-year EFS was 69.6% (95% CI, 55.2 to 80.9), which did not differ from the rate observed historically (P = .59). Seven deaths occurred (six disease-related and one second malignancy). The overall survival was 84.8% (95% CI, 71.8 to 92.4). Twenty-two patients (48%) reached dose levels ≥ 4. Nonhematologic adverse events grade ≥ 3 or cardiac adverse events grade ≥ 2 occurred in 47 of 276 (17%) courses and 30 of 46 patients (65%). CONCLUSION: DA-EPOCH-R did not improve the EFS compared with a historical control in this first prospective multisite international study of children and adolescents with PMLBL. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Adolescente , Criança , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/patologia , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Rituximab/administração & dosagem , Vincristina/administração & dosagem
11.
J Orthop Case Rep ; 11(2): 63-66, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34141673

RESUMO

INTRODUCTION: First metatarsal phalangeal joint (MTPJ) arthroplasty has a high failure rate due to aseptic loosening, which leads to bone loss. The salvage procedure is conversion to an arthrodesis, but bone loss can make obtaining screw fixation difficult. Herein, we report a unique case of revision first-metatarsal arthrodesis without the use of hardware after a failed arthroplasty. CASE REPORT: A 60-year-old women presented to us with first MTPJ pain in the setting of failed arthroplasty. We performed an arthrodesis; however, intraoperatively, hardware fixation could not be obtained due to bone loss. We utilized allograft bone struts to maintain first ray length and to hold the correct hallux position during arthrodesis maturation. CONCLUSION: Bone loss is a frequently encountered problem in revision surgery to a first MTPJ arthrodesis. An arthrodesis can be obtained without the use of hardware in scenarios where bone loss precludes screw fixation.

12.
Pediatr Blood Cancer ; 68 Suppl 2: e29009, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33818889
13.
Plast Reconstr Surg Glob Open ; 9(3): e3445, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33747686
14.
Clin Cancer Res ; 27(13): 3543-3548, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33568345

RESUMO

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. PATIENTS AND METHODS: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. RESULTS: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%-34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. CONCLUSIONS: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.See related commentary by Schulte and Eggert, p. 3507.


Assuntos
Neoplasias Pulmonares , Neuroblastoma , Quinase do Linfoma Anaplásico/genética , Criança , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Inibidores de Proteínas Quinases/efeitos adversos
15.
Cancer Chemother Pharmacol ; 86(6): 829-840, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33095287

RESUMO

PURPOSE: This phase 1 study aimed to determine the safety, tolerability and recommended phase 2 dose (RP2D) of crizotinib in combination with cytotoxic chemotherapy for children with refractory solid tumors and ALCL. METHODS: Pediatric patients with treatment refractory solid tumors or ALCL were eligible. Using a 3 + 3 design, crizotinib was escalated in three dose levels: 165, 215, or 280 mg/m2/dose BID. In Part A, patients received crizotinib oral solution (OS) in combination with topotecan and cyclophosphamide (topo/cyclo); in Part B, crizotinib OS was administered with vincristine and doxorubicin (vcr/dox). In Parts C and D, patients received topo/cyclo in combination with either crizotinib-formulated capsules (FC) or microspheres (cMS), respectively. Crizotinib pharmacokinetic evaluation was required. RESULTS: Forty-four eligible patients were enrolled, 39 were evaluable for toxicity. Parts A and B were terminated due to concerns regarding palatability and tolerability of the OS. In Part C, crizotinib, FC 215 mg/m2/dose BID, in combination with topo/cyclo was tolerated. In Part D, the maximum tolerated dose (MTD) was exceeded at 165 mg/m2/dose of crizotinib cMS. Pharmacokinetics of crizotinib in combination with chemotherapy was similar to single-agent crizotinib and exposures were not formulation dependent. CONCLUSIONS: The RP2D of crizotinib FCs in combination with cyclophosphamide and topotecan was 215 mg/m2/dose BID. The oral solution of crizotinib was not palatable in this patient population. Crizotinib cMS was palatable; however, patients experienced increased toxicity that was not explained by the relative bioavailability or exposure and warrants further investigation. CLINICAL TRIAL REGISTRY: The trial is registered as NCT01606878 at Clinicaltrials.gov.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Crizotinibe/toxicidade , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Oral , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Disponibilidade Biológica , Criança , Pré-Escolar , Crizotinibe/administração & dosagem , Crizotinibe/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/toxicidade , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lactente , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Topotecan/administração & dosagem , Topotecan/toxicidade , Vincristina/administração & dosagem , Vincristina/toxicidade , Adulto Jovem
16.
Eur J Cancer ; 139: 135-148, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32992153

RESUMO

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.


Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Criança , Desenvolvimento de Medicamentos , Epigenômica/métodos , Europa (Continente) , Humanos , Oncologia/métodos , Estados Unidos , United States Food and Drug Administration
17.
Eur J Cancer ; 136: 116-129, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32688206

RESUMO

PURPOSE: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. METHODS: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. RESULTS: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. CONCLUSION: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.


Assuntos
Antineoplásicos , Desenvolvimento de Medicamentos/organização & administração , Leucemia Mieloide Aguda/tratamento farmacológico , Oncologia/organização & administração , Pediatria/organização & administração , Adolescente , Idade de Início , Antineoplásicos/classificação , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/normas , Desenvolvimento de Medicamentos/tendências , Europa (Continente)/epidemiologia , Humanos , Agências Internacionais/organização & administração , Agências Internacionais/tendências , Cooperação Internacional , Leucemia Mieloide Aguda/epidemiologia , Oncologia/tendências , Pediatria/tendências , Análise de Sobrevida , Estados Unidos/epidemiologia , United States Food and Drug Administration/organização & administração , United States Food and Drug Administration/tendências
18.
Pediatr Blood Cancer ; 67(9): e28435, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32558190

RESUMO

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, government research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of coronavirus disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (a) the critical role that translational research has played in transforming pediatric cancer outcomes; (b) the current and potential future impact of COVID-19 on pediatric cancer research; (c) target areas of COVID-19 research that may have application in immunity, oncogenesis, and therapeutic discovery; and (d) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus , Neoplasias , Pandemias , Pneumonia Viral , Pesquisa Translacional Biomédica , Adolescente , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Feminino , Humanos , Lactente , Masculino , Neoplasias/epidemiologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/terapia , SARS-CoV-2
19.
N Engl J Med ; 382(23): 2207-2219, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32492302

RESUMO

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Infecções/etiologia , Infusões Intravenosas , Estimativa de Kaplan-Meier , Linfoma de Células B/mortalidade , Masculino , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Rituximab/efeitos adversos
20.
J Orthop ; 21: 203-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273657

RESUMO

BACKGROUND: This study evaluates the safety of foot and ankle outpatient surgeries at a freestanding ambulatory surgery centers. METHODS: A total of 1352 cases were evaluated for adverse events in a retrospective review of all foot and ankle cases performed over a 5-year period at a single center. RESULTS: The rate of adverse events was 2.3%, with 31 identified over the 5-year period (23 infections, 5 symptomatic thromboembolisms, 3 postoperative hospital transfers). DISCUSSION: The rate of postoperative adverse events in outpatient foot and ankle procedures is low. These surgeries can be performed safely in an outpatient setting at an ASC. LEVEL OF EVIDENCE: Level IV, Case Series.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA