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1.
J Neurooncol ; 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32088813

RESUMO

INTRODUCTION: Childhood, adolescent and young adult (CAYA) cancer survivors treated with cranial radiotherapy are at risk for developing subsequent meningiomas. There is insufficient evidence concerning the benefits and harms of screening for subsequent meningiomas, and uncertainty about the most appropriate clinical management of asymptomatic meningiomas. Data describing current clinical decision-making is essential to formulate surveillance recommendations. METHODS: We created an online survey to identify the current international clinical practice regarding screening for and management of subsequent asymptomatic meningiomas among CAYA cancer survivors. Fifty-nine physicians from North America and Europe with expertise relevant to meningiomas were invited to participate. RESULTS: Thirty-four physicians (58%) completed the survey. The reported number of CAYA cancer survivors that physicians are willing to screen to detect one meningioma varied widely from 0 to 750 (median 50). Physicians expressed concerns regarding harms from MRI screening, including risks of unnecessary interventions (n = 25, 73%) and overdiagnosis (n = 19, 56%). Growth pattern (n = 33, 97%), location (n = 31, 91%) and size (n = 29, 85%) were endorsed as the most important factors influencing the decision to treat asymptomatic meningiomas. A challenging location (n = 14, 52%), indolent tumor growth pattern (n = 13, 48%), and absence of symptoms (n = 12, 44%) were endorsed as the main reasons to monitor without intervention. CONCLUSIONS: There is international variation in opinions and clinical practice regarding screening for subsequent asymptomatic meningiomas among at risk CAYA cancer survivors. Decision-making regarding interventions of asymptomatic meningiomas are largely driven by clinical characteristics. These valuable insights into current clinical practice will inform surveillance guidelines for CAYA cancer survivors.

2.
J Cancer Surviv ; 13(5): 759-772, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31396878

RESUMO

PURPOSE: To facilitate the implementation of long-term follow-up (LTFU) care and improve equality of care for childhood, adolescent, and young adult (CAYA) cancer survivors, the PanCareSurFup Guidelines Working Group developed evidence-based recommendations for the organization of LTFU. METHODS: We established an international multidisciplinary guideline panel. A systematic review of the literature published from 1999 to 2017 was completed to answer six clinical questions. The guideline panel reviewed the identified studies, developed evidence summaries, appraised the quality of the body of evidence, and formulated recommendations based on the evidence, expert opinions, and the need to maintain flexibility of application across different healthcare systems. RESULTS: We provide strong recommendations based on low level evidence and expert opinions, regarding organization of LTFU care, personnel involved in LTFU care, components of LTFU care and start of LTFU care. We recommend that risk-adapted LTFU care provided under the guidance of a cancer survivorship expert service or cancer centre should be available and accessible for all CAYA cancer survivors throughout their lifespan. CONCLUSION: Despite the weak levels of evidence, successful and effective implementation of these recommendations should improve LTFU, thereby leading to better access to appropriate healthcare services and an improvement in health outcomes for CAYA cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: To improve health outcomes and quality of survivorship of current and future survivors, continued age-adapted education of survivors about the cancer, its treatment, risk of late effects, importance of health behaviours, and necessity of LTFU is important along the cancer and survivorship trajectory.

3.
Eur J Cancer ; 117: 71-83, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31260818

RESUMO

BACKGROUND: Survivors of childhood cancers are at risk of developing subsequent primary leukaemias (SPLs), but the long-term risks beyond 20 years of treatment are still unclear. We investigated the risk of SPLs in five-year childhood cancer survivors using a large-scale pan-European (PanCareSurFup) cohort and evaluated variations in the risk by cancer and demographic factors. METHODS: This largest-ever assembled cohort comprises 69,460 five-year childhood cancer survivors from 12 European countries. Standardised incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. RESULTS: One hundred fifteen survivors developed an SPL including 86 myeloid leukaemias (subsequent primary myeloid leukaemias [SPMLs]), 17 lymphoid leukaemias and 12 other types of leukaemias; of these SPLs, 31 (27%) occurred beyond 20 years from the first childhood cancer diagnosis. Compared with the general population, childhood cancer survivors had a fourfold increased risk (SIR = 3.7, 95% confidence interval [CI]: 3.1 to 4.5) of developing leukaemia, and eight leukaemias per 100,000 person-years (AER = 7.5, 95% CI: 6.0 to 9.2) occurred in excess of that expected. The risks remained significantly elevated beyond 20 years from the first primary malignancy (SIR = 2.4, 95% CI: 1.6 to 3.4). Overall, the risk ratio for SPML (SIR = 5.8, 95% CI: 4.6 to 7.1) was higher than that for other SPLs. CONCLUSIONS: We demonstrate that beyond 20 years after childhood cancer diagnosis, survivors experience an increased risk for SPLs compared with that expected from the general population. Our findings highlight the need for awareness by survivors and their healthcare providers for potential risk related to SPL.

4.
J Clin Oncol ; 37(25): 2193-2195, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31329515
5.
Cochrane Database Syst Rev ; 4: CD008205, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30985922

RESUMO

BACKGROUND: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately, the improved prognosis has been accompanied by the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors, the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies, it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. This review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate all the existing evidence on the association between antineoplastic treatment (that is, chemotherapy, radiotherapy involving the liver, surgery involving the liver and BMT) for childhood cancer and hepatic late adverse effects. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2018, Issue 1), MEDLINE (1966 to January 2018) and Embase (1980 to January 2018). In addition, we searched reference lists of relevant articles and scanned the conference proceedings of the International Society of Paediatric Oncology (SIOP) (from 2005 to 2017) and American Society of Pediatric Hematology/Oncology (ASPHO) (from 2013 to 2018) electronically. SELECTION CRITERIA: All studies, except case reports, case series, and studies including fewer than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection and 'risk of bias' assessment. The 'risk of bias' assessment was based on earlier checklists for observational studies. For the original version of the review, two review authors independently performed data extraction. For the update of the review, the data extraction was performed by one reviewer and checked by another reviewer. MAIN RESULTS: Thirteen new studies were identified for the update of this review. In total, we included 33 cohort studies including 7876 participants investigating hepatic late adverse effects after antineoplastic treatment (especially chemotherapy and radiotherapy) for different types of childhood cancer, both haematological and solid malignancies. All studies had methodological limitations. The prevalence of hepatic late adverse effects, all defined in a biochemical way, varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well-defined as alanine aminotransferase (ALT) above the upper limit of normal, indicating cellular liver injury, resulted in eight studies. In this subgroup, the prevalence of hepatic late adverse effects ranged from 5.8% to 52.8%, with median follow-up durations varying from three to 23 years since cancer diagnosis in studies that reported the median follow-up duration. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal, resulted in five studies, with a prevalence ranging from 0.9% to 44.8%. One study investigated biliary tract injury, defined as gamma-glutamyltransferase (γGT) above the upper limit of normal and above twice the upper limit of normal and reported a prevalence of 5.3% and 0.9%, respectively. Three studies investigated disturbance in biliary function, defined as bilirubin above the upper limit of normal and reported prevalences ranging from 0% to 8.7%. Two studies showed that treatment with radiotherapy involving the liver (especially after a high percentage of the liver irradiated), higher BMI, and longer follow-up time or older age at evaluation increased the risk of cellular liver injury in multivariable analyses. In addition, there was some suggestion that busulfan, thioguanine, hepatic surgery, chronic viral hepatitis C, metabolic syndrome, use of statins, non-Hispanic white ethnicity, and higher alcohol intake (> 14 units per week) increase the risk of cellular liver injury in multivariable analyses. Chronic viral hepatitis was shown to increase the risk of cellular liver injury in six univariable analyses as well. Moreover, one study showed that treatment with radiotherapy involving the liver, higher BMI, higher alcohol intake (> 14 units per week), longer follow-up time, and older age at cancer diagnosis increased the risk of biliary tract injury in a multivariable analysis. AUTHORS' CONCLUSIONS: The prevalence of hepatic late adverse effects among studies with an adequate outcome definition varied considerably from 1% to 53%. Evidence suggests that radiotherapy involving the liver, higher BMI, chronic viral hepatitis and longer follow-up time or older age at follow-up increase the risk of hepatic late adverse effects. In addition, there may be a suggestion that busulfan, thioguanine, hepatic surgery, higher alcohol intake (>14 units per week), metabolic syndrome, use of statins, non-Hispanic white ethnicity, and older age at cancer diagnosis increase the risk of hepatic late adverse effects. High-quality studies are needed to evaluate the effects of different therapy doses, time trends, and associated risk factors after antineoplastic treatment for childhood cancer.


Assuntos
Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radioterapia/efeitos adversos , Adolescente , Alanina Transaminase/metabolismo , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Humanos , Lactente , Hepatopatias , gama-Glutamiltransferase/metabolismo
6.
Lancet Oncol ; 20(1): e29-e41, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30614474

RESUMO

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.

7.
Arch Dis Child ; 104(1): 25-29, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29730641

RESUMO

OBJECTIVE: To determine the likely rate of patient randomisation and to facilitate sample size calculation for a full-scale phase III trial of varicella zoster immunoglobulin (VZIG) and aciclovir as postexposure prophylaxis against chickenpox in children with cancer. DESIGN: Multicentre pilot randomised controlled trial of VZIG and oral aciclovir. SETTING: England, UK. PATIENTS: Children under 16 years of age with a diagnosis of cancer: currently or within 6 months of receiving cancer treatment and with negative varicella zoster virus (VZV) serostatus at diagnosis or within the last 3 months. INTERVENTIONS: Study participants who have a significant VZV exposure were randomised to receive PEP in the form of VZIG or aciclovir after the exposure. MAIN OUTCOME MEASURES: Number of patients registered and randomised within 12 months of the trial opening to recruitment and incidence of breakthrough varicella. RESULTS: The study opened in six sites over a 13-month period. 482 patients were screened for eligibility, 32 patients were registered and 3 patients were randomised following VZV exposure. All three were randomised to receive aciclovir and there were no cases of breakthrough varicella. CONCLUSIONS: Given the limited recruitment to the PEPtalk2 pilot, it is unlikely that the necessary sample size would be achievable using this strategy in a full-scale trial. The study identified factors that could be used to modify the design of a definitive trial but other options for defining the best means to protect such children against VZV should be explored. TRIAL REGISTRATION NUMBER: ISRCTN48257441, EudraCT number: 2013-001332-22, sponsor: University of Birmingham.


Assuntos
Aciclovir/uso terapêutico , Soros Imunes , Neoplasias , Profilaxia Pós-Exposição/métodos , Adolescente , Antivirais/uso terapêutico , Criança , Pré-Escolar , Inglaterra , Feminino , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/isolamento & purificação , Humanos , Imunização Passiva/métodos , Masculino , Neoplasias/complicações , Neoplasias/terapia , Projetos Piloto , Resultado do Tratamento
8.
Eur J Cancer ; 103: 238-248, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30286417

RESUMO

BACKGROUND: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF. METHODS: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public. RESULTS: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors. CONCLUSIONS: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.


Assuntos
Neoplasias/terapia , Pesquisa Biomédica , Criança , Estudos de Viabilidade , Feminino , Guias como Assunto , Humanos , Masculino , Neoplasias/mortalidade , Projetos Piloto , Sobreviventes
9.
Eur J Cancer ; 102: 69-81, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30138773

RESUMO

BACKGROUND: Currently, there are between 300,000 and 500,000 childhood cancer survivors (CCSs) in Europe. A significant proportion is at high risk, and at least 60% of them develop adverse health-related outcomes that can appear several years after treatment completion. Many survivors are unaware of their personal risk, and there seems to be a general lack of information among healthcare providers about pathophysiology and natural history of treatment-related complications. This can generate incorrect or delayed diagnosis and treatments. METHOD: The Survivorship Passport (SurPass) consists of electronic documents, which summarise the clinical history of the childhood or adolescent cancer survivor. It was developed by paediatric oncologists of the PanCare and SIOPE networks and IT experts of Cineca, together with parents, patients, and survivors' organisations within the European Union-funded European Network for Cancer research in Children and Adolescents. It consists of a template of a web-based, simply written document, translatable in all European languages, to be given to each CCS. The SurPass provides a summary of each survivor's clinical history, with detailed information about the original cancer and of treatments received, together with personalised follow-up and screening recommendations based on guidelines published by the International Guidelines Harmonization Group and PanCareSurFup. RESULTS: The SurPass data schema contains a maximum of 168 variables and uses internationally approved nomenclature, except for radiotherapy fields, where a new classification was defined by radiotherapy experts. The survivor-specific screening recommendations are mainly based on treatment received and are automatically suggested, thanks to built-in algorithms. These may be adapted and further individualised by the treating physician in case of special disease and survivor circumstances. The SurPass was tested at the Istituto Giannina Gaslini, Italy, and received positive feedback. It is now being integrated at the institutional, regional and national level. CONCLUSIONS: The SurPass is potentially an essential tool for improved and more harmonised follow-up of CCS. It also has the potential to be a useful tool for empowering CCSs to be responsible for their own well-being and preventing adverse events whenever possible. With sufficient commitment on the European level, this solution should increase the capacity to respond more effectively to the needs of European CCS.


Assuntos
Sobreviventes de Câncer , Documentação , Registros Eletrônicos de Saúde , Controle de Formulários e Registros , Neoplasias/terapia , Idade de Início , Antineoplásicos/efeitos adversos , Continuidade da Assistência ao Paciente , Europa (Continente)/epidemiologia , Humanos , Neoplasias/epidemiologia , Neoplasias/patologia , Radioterapia/efeitos adversos , Medição de Risco , Fatores de Risco , Transplante de Células-Tronco/efeitos adversos , Fatores de Tempo , Tradução , Resultado do Tratamento
10.
J Clin Oncol ; 36(21): 2223-2230, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29874138

RESUMO

With improvements in cancer treatment and supportive care, a growing population of survivors of childhood cancer at risk for significant and potentially life-threatening late effects has been identified. To provide a current snapshot of the models of care from countries with varying levels of resources and health care systems, stakeholders in childhood cancer survivorship clinical care and research were identified from 18 countries across five continents. Stakeholders responded to a survey and provided a brief narrative regarding the current state of survivorship care. Findings indicate that among pediatric-age survivors of childhood cancer (allowing for differences in age cutoffs across countries), resources are generally available, and a large proportion of survivors are seen by a physician familiar with late effects in most countries. After survivors transition to adulthood, only a minority are seen by a physician familiar with late effects. Despite the need to improve communication between pediatric oncology and primary care, only a few countries have existing national efforts to educate primary care physicians, although many more reported that educational programs are in development. These data highlight common challenges and potential solutions for the lifelong care of survivors of childhood cancer. Combining risk-based and patient-oriented solutions for this population is likely to benefit both providers and patients.


Assuntos
Sobreviventes de Câncer , Assistência à Saúde , Criança , Saúde Global , Humanos , Neoplasias/mortalidade
11.
J Clin Oncol ; 36(21): 2216-2222, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29874139

RESUMO

Many childhood cancer survivors carry a significant risk for late morbidity and mortality, a consequence of the numerous therapeutic exposures that contribute to their cure. Focused surveillance for late therapy-related complications provides opportunities for early detection and implementation of health-preserving interventions. The substantial body of research that links therapeutic exposures used during treatment of childhood cancer to adverse outcomes among survivors enables the characterization of groups at the highest risk for developing complications related to specific therapies; however, methods available to optimize screening strategies to detect these therapy-related complications are limited. Moreover, the feasibility of conducting clinical trials to test screening recommendations for childhood cancer survivors is limited by requirements for large sample sizes, lengthy study periods, prohibitive costs, and ethical concerns. In addition, the harms of screening should be considered, including overdiagnosis and psychological distress. Experts in several countries have developed guideline recommendations for late effects surveillance and have collaborated to harmonize these recommendations internationally to enhance long-term follow-up care and quality of life for childhood cancer survivors. Methods used in these international efforts include systematic literature searches, development of evidence-based summaries, rigorous evaluation of the evidence, and formulation of consensus-based surveillance recommendations for each late complication. Alternate methods to refine recommendations, such as cumulative burden assessment and risk prediction and cost-effectiveness modeling, may provide novel approaches to guide survivorship care in this vulnerable population and, thus, represents a worthy objective for future international survivorship collaborations.


Assuntos
Sobreviventes de Câncer , Neoplasias/complicações , Criança , Humanos , Programas de Rastreamento/métodos , Morbidade , Neoplasias/mortalidade , Neoplasias/terapia , Guias de Prática Clínica como Assunto , Qualidade de Vida
12.
J Clin Oncol ; 36(21): 2160-2168, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29874140

RESUMO

Reproductive health is a common concern and often a source of distress for male childhood, adolescent, and young adult cancer survivors. Clinical and epidemiologic research in survivor populations has identified alkylating agent chemotherapy, testicular radiation, and surgery or radiation to the genitourinary organs, lower spine, or the hypothalamic-pituitary region as risk factors for adverse reproductive outcomes, including impaired spermatogenesis, testosterone insufficiency, and sexual dysfunction. Much of the research on male survivors has focused on the outcome of fertility, using spermatogenesis, serum gonadotropins, and paternity as the measures. However, these studies often fail to account for the clinically relevant but difficult-to-quantify aspects of fertility such as sexual function, cancer-related delayed psychosocial development, medical comorbidities, and socioeconomic concerns. Clinical and basic science research has made significant contributions to improving reproductive outcomes for survivors, with recent advancements in the areas of fertility preservation, clinical assessment of reproductive function, and treatment of adverse reproductive outcomes. Furthermore, there is an emerging qualitative literature addressing the psychosexual aspects of male reproductive health, the clinical application of which will improve quality of life for survivors. This review summarizes the current survivorship literature on reproductive health outcomes for male survivors, including the epidemiology of impaired spermatogenesis, testosterone insufficiency, and sexual dysfunction; clinical and laboratory assessment of reproductive function; and established and investigational interventions to preserve reproductive function for patients newly diagnosed and survivors. Although survivorship research has made significant contributions to improving reproductive outcomes, additional scientific progress is needed in the areas of fertility preservation, risk assessment, and psychosexual support with the aim of optimizing reproductive health for current and future survivors.


Assuntos
Sobreviventes de Câncer , Infertilidade Masculina/etiologia , Infertilidade Masculina/terapia , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Fisiológicas/terapia , Adolescente , Adulto , Humanos , Masculino , Neoplasias/mortalidade , Neoplasias/fisiopatologia , Neoplasias/terapia , Saúde Reprodutiva , Adulto Jovem
13.
J Cancer Surviv ; 12(5): 647-650, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946794

RESUMO

PURPOSE: The number of persons who have successfully completed treatment for a cancer diagnosed during childhood and who have entered adulthood is increasing over time, and former patients will become aging citizens. METHODS: Ten years ago, an expert panel met in Erice, Italy, to produce a set of principles concerning the cure and care of survivors of childhood and adolescent cancer. The result was the Erice Statement (Haupt et al. Eur J Cancer 43(12):1778-80, 2007) that was translated into nine languages. Ten years on, it was timely to review, and possibly revise, the Erice Statement in view of the changes in paediatric oncology and the number and results of international follow-up studies conducted during the intervening years. RESULTS: The long-term goal of the cure and care of a child with cancer is that he/she becomes a resilient and autonomous adult with optimal health-related quality of life, accepted in society at the same level as his/her age peers. "Cure" refers to cure from the original cancer, regardless of any potential for, or presence of, remaining disabilities or side effects of treatment. The care of a child with cancer should include complete and honest information for parents and the child. CONCLUSIONS AND IMPLICATION FOR CANCER SURVIVORS: Some members of the previous expert panel, as well as new invited experts, met again in Erice to review the Erice Statement, producing a revised version including update and integration of each of the ten points. In addition, a declaration has been prepared, by the Childhood Cancer International Survivors Network in Dublin on October 2016 (see Annex 1).


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias/mortalidade , Qualidade de Vida/psicologia , Sobreviventes/estatística & dados numéricos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Neoplasias/terapia
14.
Bone Marrow Transplant ; 53(9): 1165-1169, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29545594

RESUMO

Paediatric therapy-related acute myeloid leukaemia (t-AML) is rare and the outcome is poor. While allogeneic haematopoietic stem cell transplantation (HSCT) is generally the accepted modality of treatment, data regarding salvage chemotherapy, remission induction, conditioning regimens, transplant-related mortality and outcome is scarce. Between 2000 and2016, 36 children with t-AML were treated in seven UK paediatric HSCT centres. The most common salvage protocol for remission induction was FLAG with or without idarubicin and 28 patients were in complete morphological remission prior to BMT. Only 12 patients survived (33%). Transplant-related mortality (TRM) was the leading cause of death.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Segunda Neoplasia Primária/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Criança , Pré-Escolar , Citarabina/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Idarubicina/uso terapêutico , Masculino , Indução de Remissão/métodos , Terapia de Salvação/métodos , Análise de Sobrevida , Reino Unido , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
16.
Pediatr Nephrol ; 33(2): 215-225, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28434047

RESUMO

Chronic glomerular and tubular nephrotoxicity is reported in 20-50% and 20-25%, respectively, of children and adolescents treated with ifosfamide and 60-80% and 10-30%, respectively, of those given cisplatin. Up to 20% of children display evidence of chronic glomerular damage after unilateral nephrectomy for a renal tumour. Overall, childhood cancer survivors have a ninefold higher risk of developing renal failure compared with their siblings. Such chronic nephrotoxicity may have multiple causes, including chemotherapy, radiotherapy exposure to kidneys, renal surgery, supportive care drugs and tumour-related factors. These cause a wide range of chronic glomerular and tubular toxicities, often with potentially severe clinical sequelae. Many risk factors for developing nephrotoxicity, mostly patient and treatment related, have been described, but we remain unable to predict all episodes of renal damage. This implies that other factors may be involved, such as genetic polymorphisms influencing drug metabolism. Although our knowledge of the long-term outcomes of chronic nephrotoxicity is increasing, there is still much to learn, including how we can optimally predict or achieve early detection of nephrotoxicity. Greater understanding of the pathogenesis of nephrotoxicity is needed before its occurrence can be prevented.


Assuntos
Antineoplásicos/efeitos adversos , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Carboplatina/efeitos adversos , Criança , Cisplatino/efeitos adversos , Humanos , Ifosfamida/efeitos adversos , Nefropatias/diagnóstico , Nefropatias/terapia , Fatores de Risco , Sobreviventes , Fatores de Tempo
17.
J Natl Cancer Inst ; 110(2)2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28954302

RESUMO

Introduction: We investigate the risks of subsequent primary bone cancers after childhood and adolescent cancer in 12 European countries. For the first time, we satisfactorily address the risks beyond 40 years from diagnosis and beyond 40 years of age among all survivors. Methods: This largest-ever assembled cohort comprises 69 460 five-year survivors of cancer diagnosed before age 20 years. Standardized incidence ratios, absolute excess risks, and multivariable-adjusted relative risks and relative excess risks were calculated. All statistical tests were two-sided. Results: Overall, survivors were 21.65 times (95% confidence interval = 18.97 to 24.60 times) more likely to be diagnosed with a subsequent primary bone cancer than expected from the general population. The greatest excess numbers of bone cancers were observed after retinoblastoma, bone sarcoma, and soft tissue sarcoma. The excess number of bone cancers declined linearly with both years since diagnosis and attained age (all P < .05). Beyond 40 years from diagnosis and age 40 years, there were at most 0.45 excess bone cancers among all survivors per 10 000 person-years at risk; beyond 30 years from diagnosis and age 30 years, there were at most 5.02 excess bone cancers after each of retinoblastoma, bone sarcoma, and soft tissue sarcoma, per 10 000 person-years at risk. Conclusions: For all survivors combined and the cancer groups with the greatest excess number of bone cancers, the excess numbers observed declined with both age and years from diagnosis. These results provide novel, reliable, and unbiased information about risks and risk factors among long-term survivors of childhood and adolescent cancer.


Assuntos
Neoplasias Ósseas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Sobreviventes/estatística & dados numéricos , Adolescente , Adulto , Criança , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Osteossarcoma/epidemiologia , Retinoblastoma/epidemiologia , Sarcoma/epidemiologia , Adulto Jovem
18.
J Allergy Clin Immunol ; 141(4): 1417-1426.e1, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28780238

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants. OBJECTIVE: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αß CD3+ cells from the graft. METHODS: CD3+TCRαß+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. RESULTS: Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). CONCLUSION: CD3+TCRαß+ and CD19+ cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.


Assuntos
Antígenos CD19/imunologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Alemtuzumab/imunologia , Soro Antilinfocitário/imunologia , Bussulfano/análogos & derivados , Bussulfano/imunologia , Complexo CD3/imunologia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Estudos Retrospectivos , Tiotepa/imunologia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/imunologia
19.
J Natl Cancer Inst ; 110(6): 649-660, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165710

RESUMO

Background: Childhood cancer survivors are at risk of subsequent primary soft-tissue sarcomas (STS), but the risks of specific STS histological subtypes are unknown. We quantified the risk of STS histological subtypes after specific types of childhood cancer. Methods: We pooled data from 13 European cohorts, yielding a cohort of 69 460 five-year survivors of childhood cancer. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. Results: Overall, 301 STS developed compared with 19 expected (SIR = 15.7, 95% confidence interval [CI] = 14.0 to 17.6). The highest standardized incidence ratios were for malignant peripheral nerve sheath tumors (MPNST; SIR = 40.6, 95% CI = 29.6 to 54.3), leiomyosarcomas (SIR = 29.9, 95% CI = 23.7 to 37.2), and fibromatous neoplasms (SIR = 12.3, 95% CI = 9.3 to 16.0). SIRs for MPNST were highest following central nervous system tumors (SIR = 80.5, 95% CI = 48.4 to 125.7), Hodgkin lymphoma (SIR = 81.3, 95% CI = 35.1 to 160.1), and Wilms tumor (SIR = 76.0, 95% CI = 27.9 to 165.4). Standardized incidence ratios for leiomyosarcoma were highest following retinoblastoma (SIR = 342.9, 95% CI = 245.0 to 466.9) and Wilms tumor (SIR = 74.2, 95% CI = 37.1 to 132.8). AERs for all STS subtypes were generally low at all years from diagnosis (AER < 1 per 10 000 person-years), except for leiomyosarcoma following retinoblastoma, for which the AER reached 52.7 (95% CI = 20.0 to 85.5) per 10 000 person-years among patients who had survived at least 45 years from diagnosis of retinoblastoma. Conclusions: For the first time, we provide risk estimates of specific STS subtypes following childhood cancers and give evidence that risks of MPNSTs, leiomyosarcomas, and fibromatous neoplasms are particularly increased. While the multiplicative excess risks relative to the general population are substantial, the absolute excess risk of developing any STS subtype is low, except for leiomyosarcoma after retinoblastoma. These results are likely to be informative for both survivors and health care providers.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Segunda Neoplasia Primária/epidemiologia , Sarcoma/epidemiologia , Neoplasias de Tecidos Moles/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Adulto Jovem
20.
J Cell Sci ; 130(24): 4132-4143, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29093022

RESUMO

The Golgi is the cellular hub for complex glycosylation, controlling accurate processing of complex proteoglycans, receptors, ligands and glycolipids. Its structure and organisation are dependent on golgins, which tether cisternal membranes and incoming transport vesicles. Here, we show that knockout of the largest golgin, giantin, leads to substantial changes in gene expression but only limited effects on Golgi structure. Notably, 22 Golgi-resident glycosyltransferases, but not glycan-processing enzymes or the ER glycosylation machinery, are differentially expressed following giantin ablation. This includes near-complete loss of function of GALNT3 in both mammalian cell and zebrafish models. Giantin-knockout zebrafish exhibit hyperostosis and ectopic calcium deposits, recapitulating phenotypes of hyperphosphatemic familial tumoral calcinosis, a disease caused by mutations in GALNT3. These data reveal a new feature of Golgi homeostasis: the ability to regulate glycosyltransferase expression to generate a functional proteoglycome.


Assuntos
Glicosiltransferases/genética , Complexo de Golgi/genética , Proteínas de Membrana/genética , N-Acetilgalactosaminiltransferases/genética , Animais , Linhagem Celular , Regulação Enzimológica da Expressão Gênica , Complexo de Golgi/enzimologia , Proteínas da Matriz do Complexo de Golgi , Humanos , Mutação , Peixe-Zebra
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