RESUMO
BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.
Assuntos
Neoplasias do Sistema Nervoso Central , Terapia com Prótons , Humanos , Terapia com Prótons/métodos , Terapia com Prótons/efeitos adversos , Neoplasias do Sistema Nervoso Central/radioterapia , Criança , Adolescente , Adulto Jovem , Resultado do Tratamento , AdultoRESUMO
In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Pandemias , Consenso , OncologiaRESUMO
BACKGROUND: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. METHODS: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. FINDINGS: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. INTERPRETATION: Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. FUNDING: None.
Assuntos
Antineoplásicos , Medicamentos Essenciais , Neoplasias , Adolescente , Criança , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Oncologia , Europa (Continente) , Medicamentos Essenciais/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.
Assuntos
COVID-19/epidemiologia , Portador Sadio/epidemiologia , Neoplasias/virologia , SARS-CoV-2/genética , Adolescente , COVID-19/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Mortalidade , Neoplasias/mortalidade , Estudos Prospectivos , RNA Viral/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Reino Unido/epidemiologiaRESUMO
The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community.
Assuntos
COVID-19/patologia , Disseminação de Informação/métodos , Bibliotecas Médicas , Neoplasias/patologia , Criança , Comorbidade , Recursos em Saúde , Humanos , Sistema de Registros , SARS-CoV-2RESUMO
The traditional cancer drug development pathway is increasingly being superseded by trials that address multiple clinical questions. These are collectively termed Complex Innovative Design (CID) trials. CID trials not only assess the safety and toxicity of novel anticancer medicines but also their efficacy in biomarker-selected patients, specific cancer cohorts or in combination with other agents. They can be adapted to include new cohorts and test additional agents within a single protocol. Whilst CID trials can speed up the traditional route to drug licencing, they can be challenging to design, conduct and interpret. The Experimental Cancer Medicine Centres (ECMC) network, funded by the National Institute for Health Research (NIHR), Cancer Research UK (CRUK) and the Health Boards of Wales, Northern Ireland and Scotland, formed a working group with relevant stakeholders from clinical trials units, the pharmaceutical industry, funding bodies, regulators and patients to identify the main challenges of CID trials. The working group generated ten consensus recommendations. These aim to improve the conduct, quality and acceptability of oncology CID trials in clinical research and, importantly, to expedite the process by which effective treatments can reach cancer patients.
Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , HumanosRESUMO
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-2RESUMO
Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients' immune responses have demonstrated limited efficacy to date, despite encouraging preclinical data. Examination of AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, demonstrated an increase in the expression of Cancer-Testis Antigens (MAGE, RAGE, LAGE, SSX2 and TRAG3) on blasts and that these can be recognised by circulating antigen-specific T cells. Although the T cells have the potential to be activated by these unmasked antigens, the low arginine microenvironment created by AML blast Arginase II activity acts a metabolic brake leading to T cell exhaustion. T cells exhibit impaired proliferation, reduced IFN-γ release and PD-1 up-regulation in response to antigen stimulation under low arginine conditions. Inhibition of arginine metabolism enhanced the proliferation and cytotoxicity of anti-NY-ESO T cells against AZA/VOR treated AML blasts, and can boost anti-CD33 Chimeric Antigen Receptor-T cell cytotoxicity. Therefore, measurement of plasma arginine concentrations in combination with therapeutic targeting of arginase activity in AML blasts could be a key adjunct to immunotherapy.
Assuntos
Antígenos de Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arginase/antagonistas & inibidores , Arginina/sangue , Leucemia Mieloide/terapia , Doença Aguda , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Arginase/sangue , Arginase/metabolismo , Arginina/metabolismo , Azacitidina/administração & dosagem , Humanos , Imunoterapia/métodos , Células K562 , Leucemia Mieloide/imunologia , Leucemia Mieloide/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Vorinostat/administração & dosagemRESUMO
The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells, and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor-cell killing independently of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitized p53-defective, chemotherapy-resistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.
Assuntos
Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Reparo de DNA por Recombinação/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteases Específicas de Ubiquitina/genética , Adenina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Endogâmicos NOD , Piperidinas , Cultura Primária de Células , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Peptidase 7 Específica de Ubiquitina , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Proteases Específicas de Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed. PROCEDURE: Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described. RESULTS: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment. CONCLUSION: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Amplificação de Genes , Humanos , Quimioterapia de Indução , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc/genética , Metástase Neoplásica , Neuroblastoma/genética , Neuroblastoma/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. METHODS: Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. CONCLUSION: There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Criança , Progressão da Doença , HumanosRESUMO
Arginine is a semi-essential amino acid that plays a key role in cell survival and proliferation in normal and malignant cells. BCT-100, a pegylated (PEG) recombinant human arginase, can deplete arginine and starve malignant cells of the amino acid. Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, yet for patients with high risk or relapsed disease prognosis remains poor. We show that BCT-100 is cytotoxic to ALL blasts from patients in vitro by necrosis, and is synergistic in combination with dexamethasone. Against ALL xenografts, BCT-100 leads to a reduction in ALL engraftment and a prolongation of survival. ALL blasts express the arginine transporter CAT-1, yet the majority of blasts are arginine auxotrophic due to deficiency in either argininosuccinate synthase (ASS) or ornithine transcarbamylase (OTC). Although endogenous upregulation or retroviral transduced increases in ASS or OTC may promote ALL survival under moderately low arginine conditions, expression of these enzymes cannot prevent BCT-100 cytotoxicity at arginine depleting doses. RNA-sequencing of ALL blasts and supporting stromal cells treated with BCT-100 identifies a number of candidate pathways which are altered in the presence of arginine depletion. Therefore, BCT-100 provides a new clinically relevant therapeutic approach to target arginine metabolism in ALL.
Assuntos
Antineoplásicos/farmacologia , Arginase/farmacologia , Arginina/metabolismo , Metaboloma/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Recombinantes/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/farmacologia , Sinergismo Farmacológico , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.
Assuntos
Barreira Hematoencefálica/patologia , Movimento Celular/fisiologia , Sistema Nervoso Central/patologia , Infiltração Leucêmica/patologia , Leucócitos/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Células Cultivadas , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/secundário , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Transplante de Neoplasias , Recidiva , Transplante HeterólogoRESUMO
BACKGROUND: Magnetic resonance imaging (MRI) is routinely used as a surveillance tool to detect early asymptomatic tumour recurrence with a view to improving patient outcomes. This systematic review aimed to assess its utility in children with low-grade CNS tumours. METHODS: Using standard systematic review methods, twelve databases were searched up to January 2017. RESULTS: Seven retrospective case series studies (n = 370 patients) were included, with average follow-up ranging from 5.6 to 7 years. No randomised controlled trials (RCTs) were identified. Due to study heterogeneity only a descriptive synthesis could be undertaken. Imaging was most frequent in the first year post-surgery (with 2-4 scans) reducing to around half this frequency in year two and annually thereafter for the duration of follow-up. Diagnostic yield ranged from 0.25 to 2%. Recurrence rates ranged from 5 to 41%, with most recurrences asymptomatic (range 65-100%). Collectively, 56% of recurrences had occurred within the first year post-treatment (46% in the first 6-months), 68% by year two and 90% by year five. Following recurrence, 90% of patients underwent treatment changes, mainly repeat surgery (72%). Five-year OS ranged from 96 to 100%, while five-year recurrence-free survival ranged from 67 to 100%. None of the studies reported quality of life measures. CONCLUSION: This systematic review highlights the paucity of evidence currently available to assess the utility of MRI surveillance despite it being routine clinical practice and costly to patients, their families and healthcare systems. This needs to be evaluated within the context of an RCT.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Detecção Precoce de Câncer , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico por imagem , Adolescente , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Detecção Precoce de Câncer/métodos , Humanos , Lactente , Recém-Nascido , Gradação de Tumores , Adulto JovemRESUMO
New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.
Assuntos
Antineoplásicos/uso terapêutico , Legislação de Medicamentos , Neoplasias/tratamento farmacológico , Medicina de Precisão , Adolescente , Antineoplásicos/farmacologia , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Descoberta de Drogas/legislação & jurisprudência , Europa (Continente) , Humanos , Lactente , Recém-NascidoRESUMO
Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML.
Assuntos
Arginase/uso terapêutico , Arginina/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Adolescente , Idoso , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Citarabina/uso terapêutico , Terapia Enzimática , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Células Tumorais Cultivadas , Adulto JovemRESUMO
A recent case of advanced, recurrent juvenile nasopharyngeal angiofibroma (JNA) at our institution has highlighted the limited evidence regarding adjunctive treatment. We present the case of a 10-year-old boy who is the first to undergo multiple-staged surgical resections alongside vincristine treatment. We performed a review of the literature analyzing the roles of radiation therapy, cytotoxic drugs, and novel targeted agents in JNA relapse. Small cohort studies suggest radiotherapy and flutamide are the most rational treatment options for residual and recurrent JNA. Our review highlights the need for further research into the management of primary and recurrent JNA.