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1.
Blood ; 144(11): 1193-1205, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-38917355

RESUMO

ABSTRACT: Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Ataxia Telangiectasia , Mutação em Linhagem Germinativa , Neoplasias Hematológicas , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Criança , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/mortalidade , Masculino , Feminino , Adolescente , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Pré-Escolar , Lactente , Adulto Jovem , Adulto
2.
Genes Chromosomes Cancer ; 63(9): e23269, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39291932

RESUMO

INTRODUCTION: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a high risk form of ALL associated with dismal outcomes in the pre-tyrosine kinase inhibitor (TKI) era. Addition of a TKI to chemotherapy improves outcomes. Therefore, testing for the presence of the Philadelphia chromosome by at least two methods at the time of diagnosis is critical. Diagnostic testing may include karyotype, fluorescent in situ hybridisation (FISH), and RT-PCR for the BCR::ABL1 transcript. The significance of low-level BCR::ABL1 transcript by RT-PCR in the absence of the Philadelphia chromosome on karyotype or by FISH is unknown. METHODS: This is a retrospective review of children diagnosed with acute leukemia at our institution from 2010 to 2020. Those positive for the BCR::ABL1 transcript by qualitative RT-PCR, and negative for t(9;22) by karyotype or FISH were analyzed for demographics, cytogenetic and molecular features at diagnosis and relapse, treatment and outcomes. The Kaplan-Meier method was used to estimate event-free and overall survival. RESULTS: Forty-seven of 306 (15%) patients with Ph- ALL had low-level BCR::ABL1 detected by RT-PCR. Most (77%) had B-cell ALL. The e1a2 transcript was detected most frequently, in 43 (91%) patients. BCR::ABL1 was quantifiable in 12/43 (28%) patients, with a median of 0.0008% (range 0.0003-0.095%). Seven patients (15%) relapsed. No patient with low-level BCR::ABL1 at diagnosis developed Ph + ALL at relapse. There was no difference in 5-year event-free (77% versus 81%, p = 0.407) or overall survival (86% versus 91%, p = 0.3) between children with low-level BCR::ABL1 (n = 47) and those without (n = 259). CONCLUSION: BCR::ABL1 low-level positivity in children with newly diagnosed Ph- ALL is a relatively common finding and did not adversely affect outcome for patients treated using a contemporary risk-adapted approach.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Masculino , Feminino , Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pré-Escolar , Adolescente , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Lactente , Cromossomo Filadélfia
3.
Br J Clin Pharmacol ; 90(7): 1615-1626, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38532641

RESUMO

AIMS: The potential harm associated with medication errors is widely reported, but data on actual harm are limited. When actual harm has been measured, assessment processes are often poorly described, limiting their ability to be reproduced by other studies. Our aim was to design and implement a new process to assess actual harm resulting from medication errors in paediatric inpatient care. METHODS: Prescribing errors were identified through retrospective medical record reviews (n = 26 369 orders) and medication administration errors through direct observation (n = 5137 administrations) in a tertiary paediatric hospital. All errors were assigned potential harm severity ratings on a 5-point scale. Multidisciplinary panels reviewed case studies for patients assigned the highest three potential severity ratings and determined the following: actual harm occurrence and severity level, plausibility of a link between the error(s) and identified harm(s) and a confidence rating if no harm had occurred. RESULTS: Multidisciplinary harm panels (n = 28) reviewed 566 case studies (173 prescribing related and 393 administration related) and found evidence of actual harm in 89 (prescribing = 22, administration = 67). Eight cases of serious harm cases were found (prescribing = 1, administration = 7) and no cases of severe harm. The panels were very confident in 65% of cases (n = 302) where no harm was found. Potential and actual harm ratings varied. CONCLUSIONS: This harm assessment process provides a systematic method for determining actual harm from medication errors. The multidisciplinary nature of the panels was critical in evaluating specific clinical, therapeutic and contextual considerations including care delivery pathways, therapeutic dose ranges and drug-drug and drug-disease interactions.


Assuntos
Hospitais Pediátricos , Erros de Medicação , Humanos , Erros de Medicação/estatística & dados numéricos , Erros de Medicação/prevenção & controle , Criança , Estudos Retrospectivos , Hospitais Pediátricos/normas , Pacientes Internados , Pré-Escolar , Lactente
4.
Haematologica ; 108(12): 3278-3286, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37021527

RESUMO

Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).


Assuntos
Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Metotrexato/uso terapêutico , Quimioterapia de Indução/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
5.
Calcif Tissue Int ; 112(5): 592-602, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36810677

RESUMO

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol.


Assuntos
Cistos Ósseos Aneurismáticos , Conservadores da Densidade Óssea , Hipercalcemia , Humanos , Criança , Denosumab/uso terapêutico , Cistos Ósseos Aneurismáticos/tratamento farmacológico , Cistos Ósseos Aneurismáticos/cirurgia , Hipercalcemia/tratamento farmacológico , Austrália , Conservadores da Densidade Óssea/uso terapêutico , Coluna Vertebral/patologia
6.
Genes Chromosomes Cancer ; 61(2): 81-93, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34687117

RESUMO

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of ß-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.


Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias , Adolescente , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Lactente , Recém-Nascido , Neoplasias/epidemiologia , Neoplasias/genética , Sequenciamento do Exoma
7.
Br J Cancer ; 127(5): 908-915, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35650277

RESUMO

BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Proteínas de Fusão bcr-abl/genética , Humanos , Imunoglobulinas , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos de Linfócitos T/genética
8.
Haematologica ; 107(3): 635-643, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33567813

RESUMO

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.


Assuntos
Estudo de Associação Genômica Ampla , Leucemia-Linfoma Linfoblástico de Células Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália , Criança , Humanos , Injeções Espinhais , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Risco
9.
BMC Cancer ; 22(1): 985, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109702

RESUMO

BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children's general and cancer-related health-related quality of life (HRQoL) and parents' emotional well-being. METHODS: Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. RESULTS: Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1-213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children's HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. CONCLUSIONS: It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.


Assuntos
Pancreatite , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Criança , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Inquéritos e Questionários
10.
Pediatr Blood Cancer ; 69(11): e29901, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35989458

RESUMO

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m2 /day and cyclophosphamide at 330-400 mg/m2 /day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3 weeks, were nelarabine 650 mg/m2 /day, etoposide 100 mg/m2 /day, and cyclophosphamide 400 mg/m2 /day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.


Assuntos
Linfoma não Hodgkin , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Criança , Ciclofosfamida/efeitos adversos , Etoposídeo/efeitos adversos , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Nucleosídeos/uso terapêutico , Néctar de Plantas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Recidiva
11.
Med J Aust ; 216(6): 312-319, 2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35201615

RESUMO

INTRODUCTION: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19. There remains a paucity of data regarding the immune response to COVID-19 vaccines in immunosuppressed paediatric populations, with data suggestive of reduced immunogenicity of the vaccine in immunocompromised adults. RECOMMENDATIONS: Considering the safety profile of mRNA COVID-19 vaccines and the increased risk of severe COVID-19 in immunocompromised children and adolescents, COVID-19 vaccination is strongly recommended for this at-risk population. We provide a number of recommendations regarding COVID-19 vaccination in this population where immunosuppressive, chemotherapeutic and/or targeted biological agents are used. These include the timing of vaccination in patients undergoing active treatment, management of specific situations where vaccination is contraindicated or recommended under special precautions, and additional vaccination recommendations for severely immunocompromised patients. Finally, we stress the importance of upcoming clinical trials to identify the safest and most efficacious vaccination regimen for this population. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This consensus statement provides recommendations for COVID-19 vaccination in children and adolescents aged ≥ 5 years with cancer and immunocompromising non-malignant haematological conditions, based on evidence, national and international guidelines and expert opinion. ENDORSED BY: The Australian and New Zealand Children's Haematology/Oncology Group.


Assuntos
COVID-19 , Hematologia , Neoplasias , Adolescente , Austrália/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Criança , Pré-Escolar , Humanos , Neoplasias/terapia , Nova Zelândia/epidemiologia , Vacinação
12.
Orbit ; 41(6): 680-686, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35938374

RESUMO

PURPOSE: The aim of this study is to report two cases of paediatric Yolk sac tumours (YST) of the orbit and sinonasal tract, with a major review on the subject. METHODS: Two case reports along with a comprehensive retrospective literature review of all English language publications between 1974 and 2021 is presented. Literature review examined the demographics, clinical presentation and diagnostic and prognostic factors of extragonadal YSTs of the orbit and sinonasal tract. RESULTS: Orbit and sinuses are rare sites for YST, with only 25 paediatric cases reported in the literature. Extragonadal yolk sac tumours carry a significantly worse outcome than those localised to the gonads, with the 5-year survival of 66% and 81-89%, respectively. Our review found the median age of presentation to be 18 months (18 months for males and 24 months for females), and females are more commonly affected. The most common presentations were proptosis, facial swelling and ophthalmoplegia. Treatments and therefore outcomes varied in the cases due to the large time period. Of the cases reported in the last 10 years, all patients with data provided were alive and disease-free at follow-up. CONCLUSION: Sino-orbital yolk sac tumours are rare and have variable presentations, dependent on the extent of local invasion. Early diagnosis and treatment with multimodal therapy are paramount in having improved overall survival.


Assuntos
Tumor do Seio Endodérmico , Exoftalmia , Seios Paranasais , Masculino , Feminino , Humanos , Criança , Lactente , Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/terapia , Tumor do Seio Endodérmico/patologia , Estudos Retrospectivos , Terapia Combinada , Seios Paranasais/patologia
13.
Br J Haematol ; 193(6): 1172-1177, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33529389

RESUMO

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Inotuzumab Ozogamicina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras , Aloenxertos , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Taxa de Sobrevida
14.
Br J Haematol ; 193(1): 171-175, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33620089

RESUMO

Disease relapse is the greatest cause of treatment failure in paediatric B-cell acute lymphoblastic leukaemia (B-ALL). Current risk stratifications fail to capture all patients at risk of relapse. Herein, we used a machine-learning approach to identify B-ALL blast-secreted factors that are associated with poor survival outcomes. Using this approach, we identified a two-gene expression signature (CKLF and IL1B) that allowed identification of high-risk patients at diagnosis. This two-gene expression signature enhances the predictive value of current at diagnosis or end-of-induction risk stratification suggesting the model can be applied continuously to help guide implementation of risk-adapted therapies.


Assuntos
Quimiocinas/genética , Interleucina-1beta/genética , Proteínas com Domínio MARVEL/genética , Aprendizado de Máquina/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Doença Aguda , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Valor Preditivo dos Testes , Recidiva , Medição de Risco/normas , Análise de Sobrevida , Transcriptoma/genética , Falha de Tratamento
15.
Cancer ; 126(4): 701-716, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31821552

RESUMO

Effective communication is challenging in childhood cancer, where decisions carry unpredictable and life-threatening implications. We aimed to describe patients' experiences of communicating with clinicians during treatment of childhood cancer. A systematic review of qualitative studies to April 2019 was performed. Eligible studies included patients diagnosed with cancer at age ≤ 18 years and reported their perspectives of communicating with clinicians during treatment of childhood cancer. Data were extracted from primary studies for thematic synthesis. From 101 articles across 25 countries involving 1870 participants who were diagnosed with cancer between ages 3 to 18 years, we identified 6 themes: 1) rendered invisible and powerless (displaced and undermined by adult authority; betrayed and distrustful; feeling neglected; helpless and intimidated; disempowered by lack of information); 2) fear and worry for the future (paralyzed by devastating news; uncertainty, anticipation, and dread; broaching intimate and private topics); 3) burdened with responsibility (pressured and unprepared; balancing external expectations; protecting hope); 4) therapeutic patient-provider relationships (emotional support and encouragement; validated personhood and companionship); 5) safety in trust (truthfulness and transparency; prepared by awareness and understanding; reassured by reliable expertise; depending on adults for protection and difficult decisions; security in expressing opinions and needs); and 6) empowerment and assertive agency (right to individual knowledge and choice; control over own life; partnership and respect; enhancing capacity for self-management). During treatment of childhood cancer, patients gain a sense of respect, safety, and control when they feel clinicians address their information and developmental needs. However, communication that is perceived to be parent-centered can be disempowering. Promoting child agency and partnership may improve care and outcomes for children with cancer.


Assuntos
Comunicação , Neoplasias/terapia , Pais/psicologia , Relações Médico-Paciente , Pesquisa Qualitativa , Adolescente , Criança , Pré-Escolar , Família , Feminino , Esperança , Humanos , Masculino , Neoplasias/psicologia , Confiança
16.
Blood ; 132(3): 264-276, 2018 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-29720486

RESUMO

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.


Assuntos
Leucemia Aguda Bifenotípica/diagnóstico , Leucemia Aguda Bifenotípica/terapia , Adolescente , Biomarcadores , Biomarcadores Tumorais , Criança , Pré-Escolar , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Aguda Bifenotípica/etiologia , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
17.
Pediatr Blood Cancer ; 67(5): e28112, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31944549

RESUMO

BACKGROUND: In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. PROCEDURE: This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. RESULTS: Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. CONCLUSIONS: Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.


Assuntos
Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/farmacocinética , Biomarcadores Tumorais/sangue , Exotoxinas/administração & dosagem , Exotoxinas/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adolescente , Toxinas Bacterianas/efeitos adversos , Criança , Pré-Escolar , Exotoxinas/efeitos adversos , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Recidiva
18.
Int J Qual Health Care ; 32(8): 511-516, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-32761121

RESUMO

OBJECTIVE: The efficiency-thoroughness trade-off (ETTO) principle proposes that people and organizations are often required to make a trade-off between being efficient and being thorough, as it is difficult to be both efficient and thorough at the same time. This study aimed to compare pre- electronic medication management system (EMMS) expectation of how an EMMS is likely to impact on efficiency and thoroughness to post-EMM experiences of an EMMS and the ETTO. DESIGN: Qualitative interview study. SETTING: A paediatric oncology cancer centre in a large paediatric tertiary teaching hospital in Sydney, Australia. PARTICIPANTS: Forty-four semi-structured interviews with doctors, nurses and pharmacists six months prior to and two years following implementation of an EMMS. RESULTS: Prior to EMM implementation, staff identified a number of areas of work where both efficiency and thoroughness were expected to improve with EMM. These included ease of accessibility of the medication record, and organization and legibility of medication information. Following EMMS implementation, staff reported improvements in these areas. However, the EMMS was perceived to drive thoroughness (safety) benefits at the expense of efficiency (time). Measures to improve safety in the EMMS enforced processes that required time, such as medication double-checking procedures. CONCLUSIONS: Overall, staff were aware of the competitive interplay between thoroughness and efficiency and reported that introduction of an EMMS had imposed processes that favoured improvements in thoroughness at the expense of efficiency.


Assuntos
Hospitais de Ensino , Neoplasias , Austrália , Criança , Eletrônica , Humanos , Neoplasias/tratamento farmacológico , Pesquisa Qualitativa
19.
BMC Med Inform Decis Mak ; 20(1): 193, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795356

RESUMO

BACKGROUND: There are serious safety risks associated with chemotherapy, often associated with interdependencies in regimens administered over months or years. Various strategies are used to manage these risks. Computerized provider order entry (CPOE) systems are also implemented to improve medication safety. Little is known regarding the effect of CPOE on how clinicians manage chemotherapy interdependencies and their associated safety strategies. METHODS: We conducted a multi-method qualitative study in a paediatric hospital. We analysed 827 oncology incidents reported following CPOE implementation and carried out semi-structured interviews with doctors (n = 10), nurses (n = 6), a pharmacist, and oncology CPOE team members (n = 2). Results were interpreted according to safety models (ultra-safe, high-reliability organisations [HROs], or ultra-adaptive). RESULTS: Incident reports highlighted two interrelated types of interdependencies: those within organisation of clinical activities and those inherent in chemotherapy regimens. Clinicians reported strategies to address chemotherapy risks and interdependencies. These included rigid rules and 'no go' contexts for treatment to proceed, typical of the ultra-safe model; use of time (e.g. planning only so far ahead) and sensitivity to operations, typical of HROs. We identified three different time horizons in CPOE use in relation to patients' treatments: life-long, the whole regimen, and the 'here and now'. CPOE supported ultra-safe strategies through automation and access to rules/standardisation, but also created difficulties and contributed to incidents. It supported the 'here and now' better than a life-long or whole regimen view of a patient treatment. Sensitivity to operations was essential to anticipate and resolve uncertainties, hazards, CPOE limitations, and mismatches between CPOE processes and workflow in practice. CONCLUSIONS: Within oncology, CPOE appears to move the 'mix' of risk strategies towards ultra-safe models of safety and protocol-mandated care. However, in order to operate ultra-safe strategies embedded in CPOE and stay on protocol it is essential for clinicians to be thoughtful and show sensitivity to operations in CPOE use. CPOE design can be advanced by better consideration of mechanisms to support interdependencies.


Assuntos
Antineoplásicos/uso terapêutico , Sistemas de Informação em Farmácia Clínica/normas , Sistemas de Apoio a Decisões Clínicas/normas , Hospitais Pediátricos/estatística & dados numéricos , Sistemas de Registro de Ordens Médicas , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Criança , Humanos , Pesquisa Qualitativa , Reprodutibilidade dos Testes , Fluxo de Trabalho
20.
J Med Genet ; 55(12): 785-793, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30287599

RESUMO

Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8.5%-35.5% of patients with childhood cancer carried clinically relevant germline variants. Analysis of 52 autosomal dominant cancer predisposition genes assumed common to all six studies showed that 5.5%-25.8% of patients with childhood cancer carried pathogenic or likely pathogenic germline variants in at least one of these genes. When only non-central nervous system solid tumours (excluding adrenocortical carcinomas) were considered, 8.5%-10.3% of the patients carried pathogenic or likely pathogenic germline variants in at least one of 52 autosomal dominant cancer predisposition genes. There was a lack of concordance between the genotype and phenotype in 33.3%-57.1% of the patients reported with pathogenic or likely pathogenic germline variants, most of which represented variants in autosomal dominant cancer predisposition genes associated with adult onset cancers. In summary, germline genetic testing in patients with childhood cancer requires clear definition of phenotypes and genes considered for interpretation, with potential to inform and broaden childhood cancer predisposition syndromes.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias/diagnóstico , Neoplasias/genética , Fatores Etários , Biomarcadores Tumorais , Criança , Estudos de Associação Genética/métodos , Variação Genética , Genótipo , Humanos , Neoplasias/mortalidade , Fenótipo
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