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Understanding the regulatory mechanisms of gene expression is a crucial objective in genomics. Although the DNA sequence near the transcription start site (TSS) offers valuable insights, recent methods suggest that analyzing only the surrounding DNA may not suffice to accurately predict gene expression levels. We developed GENet (Gene Expression Network from Histone and Transcription Factor Integration), a novel approach that integrates essential regulatory signals from transcription factors and histone modifications into a graph-based model. GENet extends beyond simple DNA sequence analysis by incorporating additional layers of genetic control, which are vital for determining gene expression. Our method markedly enhances the prediction of mRNA levels compared to previous models that depend solely on DNA sequence data. The results underscore the significance of including comprehensive regulatory information in gene expression studies. GENet emerges as a promising tool for researchers, with potential applications extending from fundamental biological research to the development of medical therapies.
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Redes Reguladoras de Genes , Código das Histonas , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Código das Histonas/genética , Humanos , Histonas/genética , Histonas/metabolismo , Regulação da Expressão Gênica , Sítio de Iniciação de Transcrição , Modelos GenéticosRESUMO
OBJECTIVE: More than 95% of melanomas in Australia are caused by UV radiation from the sun. Young adults are particularly at risk, with 18-24-year-olds spending more time in the sun and protecting their skin less than older adults. A new mass media campaign was delivered in New South Wales, Australia, to motivate this hard-to-reach group to protect their skin from harmful UV radiation. This paper shares learnings from this campaign for public health educators working across diverse fields. PROGRAM: Guided by audience research and testing, the campaign combined fear-based and self-efficacy messaging. UV radiation was portrayed as arrows descending from the sky, transforming it into a visible and ever-present threat. High-reach channels such as cinema, outdoor advertising, online videos, audio apps and social media were used to reach the audience. METHODS: The campaign was evaluated through an online tracking survey (n = 750, 18-24-year-olds) measuring prompted recognition, message take-out, key diagnostics, and self-reported sun protection intentions and behaviours. RESULTS: The evaluation found that 57% of survey participants recognised the campaign when prompted. Among those that recognised the campaign, 76% said they had used sun protection when outdoors over the summer campaign period (vs 64% of non-recognisers, p < 0.05), and 45% said they had adopted at least three of the five sun protection behaviours (Slip, Slop, Slap, Seek and Slide) 'always' or 'often' (vs. 36% of non-recognisers, p < 0.05). LESSONS LEARNT: A mass-media campaign that aimed to elicit emotional (fear) and cognitive (perceived efficacy) responses and which drew upon social and heuristic cues was associated with greater self-reported sun protection among the target audience. Delivering a combination of message strategies simultaneously within a campaign tailored to young adults may be more effective than adopting a more singular focus.
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INTRODUCTION: Radiologist shortages threaten the sustainability of breast cancer screening programmes. Artificial intelligence (AI) products that can interpret mammograms could mitigate this risk. While previous studies have suggested this technology has accuracy comparable to radiologists most have been limited by using 'enriched' datasets and/or not considering the interaction between the algorithm and human readers. This study will address these limitations by comparing the accuracy of a workflow using AI alongside radiologists on a large consecutive cohort of examinations from a breast cancer screening programme. The study will combine the strengths of a large retrospective design with the benefit of prospective data collection. It will test this technology without risk to screening programme participants nor the need to wait for follow-up data. With a sample of 2 years of consecutive screening examinations, it is likely the largest test of this technology to date. The study will help determine whether this technology can safely be introduced into the BreastScreen New South Wales (NSW) population-based screening programme to address radiology workforce risks without compromising cancer detection rates or increasing false-positive recalls. METHODS AND ANALYSIS: A retrospective, consecutive cohort of digital mammography screens from 658 207 examinations from BreastScreen NSW will be reinterpreted by the Lunit Insight MMG AI product. The cohort includes 4383 screen-detected and 1171 interval cancers. The results will be compared with radiologist single reading and the AI results will also be used to replace the second reader in a double-reading model. New adjudication reading will be performed where the AI disagrees with the first reader. Recall rates and cancer detection rates of combined AI-radiologist reading will be compared with the rates obtained at the time of screening. ETHICS AND DISSEMINATION: This study has ethical approval from the NSW Health Population Health Services Research Ethics Committee (2022/ETH02397). Findings will be published in peer-reviewed journals and presented at conferences. The findings of this evaluation will be provided to programme managers, governance bodies and other stakeholders in Australian breast cancer screening programmes.
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Inteligência Artificial , Neoplasias da Mama , Detecção Precoce de Câncer , Mamografia , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico , Feminino , Mamografia/métodos , New South Wales , Detecção Precoce de Câncer/métodos , Estudos Retrospectivos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Projetos de PesquisaRESUMO
AIM: To understand the current usage of eviQ Cancer Treatments Online (www.eviQ.org.au), an Australian, open-access website providing evidence-based and consensus-driven cancer treatment protocols and information, and the extent to which it is meeting its intended outcomes and providing value to its users. METHODS: A mixed-method evaluation was conducted in 2020-2022 which included a review of key program documentation and website usage data, and delivery of a focused online survey to its users. RESULTS: In 2022, 329 clinicians representing all Australian states and territories contributed to eviQ content development and review. eviQ content continues to grow with a 15.2% increase in total content from 2019 to 2022. eviQ website users continue to grow with 90,000 total monthly users in 2022, representing a 166% increase from 2018. The proportion of international users compared to Australian users continues to grow with 57% of total users in Australia and 43% international in 2022. Of 466 survey responses, the most cited reason for eviQ use was for information on side effects/toxicity (67%). Ninety-three percent (93%) of respondents either agreed or strongly agreed that eviQ contributed to both health professionals providing the best evidence-based treatment and care and improving the standardization of treatment and care provided. CONCLUSION: eviQ is embedded in Australian clinical practice, highly valued, and relied upon by users. Users agree that eviQ has a positive impact on patients by supporting the delivery of evidence-based treatment and that eviQ contributed to patients' improved health outcomes and quality of life. eviQ's increasing international usage should be explored.
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Medicina Baseada em Evidências , Internet , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Austrália , Medicina Baseada em Evidências/métodos , Inquéritos e QuestionáriosRESUMO
Background: An increasing number of people are using vapes (e-cigarettes), and with growing evidence of associated harms, there is a need for acceptable cessation support and interventions. Smartphone apps for health and well-being have increased in popularity and use. Limited published literature assesses the potential of apps to support vaping cessation. Objective: A systematic search of vaping cessation apps currently available in Australia for iOS and Android platforms was conducted. Apps were assessed against established health app assessment tools for quality and behavior change potential. Methods: A systematic search through the Australian Apple iTunes and Google Play stores was conducted using the search terms "vape"; "vaping"; "e-cigarette"; and "cessation," "quit," or "quitting" in May 2023. Only apps that encouraged the cessation of vaping were included. App descriptions were reviewed to determine if they were relevant for inclusion in this study, and relevant apps were downloaded onto the appropriate mobile device for review. The Mobile App Rating Scale (MARS) was used to rate the quality (engagement, functionality, aesthetics, and information) of the apps using an overall score out of 5. The App Behavior Change Scale (ABACUS) was used to assess the behavior change potential of each app using a score out of 21. Results: An initial search of the app stores yielded 220 Android apps and 124 iOS apps. Screening against the inclusion criteria left 20 iOS apps and 10 Android apps for review. Six apps were available on both operating systems, and these were downloaded, reviewed, and reported separately for each operating system. The average MARS score for all apps assessed in this review was 3.1 (SD 0.41) out of 5. The reviewed apps overall performed well for the MARS elements relating to functionality, such as ease of use and navigation, but had the lowest scores for information-related elements, such as credibility. The number of ABACUS behavior change features per app ranged from 0 to 19 out of 21, with a mean of 8.9 (SD 4.51). The apps commonly included information-related features, such as requesting baseline information. The least common behavior change features were those relating to goal-setting, such as asking about the user's willingness for behavior change and providing feedback on current actions in comparison to future goals. Conclusions: The identified vaping cessation apps had moderate levels of quality and some behavior change components. Future vaping cessation apps could benefit from including more features that are known to support behavior change, such as goal-setting, to improve the potential benefit of these apps to support people to stop vaping. As guidelines for vaping cessation continue to be established, future apps need to reference these in their development.
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Aplicativos Móveis , Vaping , Humanos , Aplicativos Móveis/normas , Aplicativos Móveis/estatística & dados numéricos , Aplicativos Móveis/tendências , Vaping/psicologia , Vaping/tendências , Austrália , Abandono do Hábito de Fumar/métodos , Abandono do Hábito de Fumar/psicologiaRESUMO
Health practitioners often insert and maintain central venous access devices (CVADs) as part of cancer care. One in four CVADs prematurely fail, which is associated with increased mortality, morbidity and a negative impact on quality of life. To support implementation of updated guidelines, eviQ Education developed a comprehensive, peer-reviewed, evidence-based CVADs eLearning package. An evaluation indicated that the eLearning supported clinicians' practice and increased knowledge and clinical competency in CVAD insertion and management.
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Instrução por Computador , Neoplasias , Humanos , Qualidade de Vida , Competência Clínica , Escolaridade , Avaliação de Resultados da Assistência ao Paciente , Neoplasias/terapiaRESUMO
Effective eLearning design takes into account the learning needs and styles of users. eviQ Education, a program of the Cancer Institute NSW, considered evidence from user data to develop a range of clinical education resources in formats informed by user preferences, including mini-modules, videos and webinars. Through the website and mobile app, content is available on-demand, supporting health professionals to learn anytime, anywhere, on any device.
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Educação a Distância , Aprendizagem , Oncologia , Escolaridade , Academias e InstitutosRESUMO
Oncology clinicians must participate in continuing professional development (CPD) to stay up to date with best practice. The Cancer Institute NSW eviQ Education program produces evidence-based, peer-reviewed eLearning resources for oncology professionals. In response to user feedback, eviQ Education trialled a mobile app, EdApp, to improve accessibility of self-directed CPD materials. Following a pilot, users indicated that the EdApp improved CPD accessibility and user experience. EdApp will continue to be used to support evidence-based practice.
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Aplicativos Móveis , Humanos , Escolaridade , Oncologia , Academias e Institutos , Pessoal de SaúdeRESUMO
Purpose: To assess the mental health conditions, as indicated by mental health service contact in adolescents and young adults (AYAs) diagnosed with cancer in New South Wales (NSW) and associations with cancer mortality. Methods: In 3998 NSW AYAs diagnosed with cancer in 2005-2017, mental health service contacts were obtained from hospital inpatient records and specified medical and pharmaceutical insurance claims. Odds of postcancer mental health contact were assessed by precancer mental contacts using logistic regression adjusted for sociodemographic and cancer characteristics. The risk of cancer-specific mortality related to postcancer mental health contacts was estimated using competing risk regression. Results: The prevalence of mental health service contacts in the 5 years postcancer diagnosis was 27.0%, higher than the corresponding precancer prevalence of 21.4%. The most common mental health conditions were depression and anxiety. The odds of having a mental health contact postcancer diagnosis were higher in patients with a precancer mental health service contact (adjusted odds ratio 5.69, confidence intervals [95% CIs]: 4.90-6.75). The 5-year cancer-specific survival was 87.9% (95% CI: 85.8-89.8) for patients with a mental health service contact postcancer, which was lower than the 93.9% (95% CI: 93.0-94.7) for patients without this contact. The subhazard ratio (SHR) for cancer mortality in patients having mental health service contact postcancer diagnosis was 1.67 (95% CI: 1.29-2.15), adjusted for sociodemographic characteristics, cancer stage, and precancer mental health status. Conclusion: The prevalence of mental health service contact increased after a cancer diagnosis. Mental health care should be a continued priority for AYA cancer patients, particularly for high-risk groups.
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Serviços de Saúde Mental , Neoplasias , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Neoplasias/mortalidade , Neoplasias/epidemiologia , New South Wales/epidemiologia , Serviços de Saúde Mental/estatística & dados numéricos , AdultoRESUMO
BACKGROUND: Australian age-standardized incidence and death rates for liver cancer are lower than world averages, but increasing as in other economically advanced western countries. World Health Organization emphasizes the need to address sociodemographic disparities in cancer risk. A more detailed sociodemographic risk profiling was undertaken for liver cancer in New South Wales (NSW) by diagnostic stage, than possible with NSW Cancer Registry (NSWCR) alone, by incorporating linked data from the Australian Bureau of Statistics (ABS). The purpose was to inform targeting and monitoring of cancer services. METHODS: The ABS manages the Multi-Agency Data Integration Project (MADIP) which includes a wide range of health, educational, welfare, census, and employment data. These data were linked at person level to NSWCR liver cancer registrations for the period post 2016 census to December 2018. De-identified data were analyzed. Sex-specific age-adjusted odds ratios (95%CIs) of liver cancer were derived using logistic regression by age, country of birth, residential remoteness, proficiency in spoken English, household income, employment status, occupation type, educational attainment, sole person household, joblessness, socioeconomic status, disability status, multimorbidity, and other health-related factors, including GP consultations. These data complement the less detailed sociodemographic data available from the NSWCR, with alignment of numerators and population denominators for accurate risk assessment. RESULTS: Results indicate liver cancer disproportionately affects population members already experiencing excess social and health disadvantage. Examples where 95% confidence intervals of odds ratios of liver cancer were elevated included having poor English-speaking proficiency, limited education, housing authority tenancy, living in sole-person households, having disabilities, multiple medicated conditions, and being carers of people with a disability. Also, odds of liver cancer were higher in more remote regions outside major cities, and in males, with higher odds of more advanced cancer stages (degrees of spread) at diagnosis in more remote regions. CONCLUSIONS: Linked data enabled more detailed risk profiling than previously possible. This will support the targeting of cancer services and benchmarking.
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Neoplasias Hepáticas , Web Semântica , Masculino , Feminino , Humanos , New South Wales/epidemiologia , Austrália/epidemiologia , Estudos de Coortes , Prognóstico , Neoplasias Hepáticas/epidemiologia , Censos , Modelos LogísticosRESUMO
BACKGROUND: Paediatric precision oncology aims to match therapeutic agents to driver gene targets. We investigated whether parents and patients regret participation in precision medicine trials, particularly when their hopes are unfulfilled. METHODS: Parents and adolescent patients completed questionnaires at trial enrolment (T0) and after receiving results (T1). Parents opted-in to an interview at T1. Bereaved parents completed a questionnaire 6-months post-bereavement (T1B). We analysed quantitative data with R and qualitative data thematically with NVivo, before integrating all data for interpretation. RESULTS: 182 parents and 23 patients completed T0; 108/182 parents and 8/23 patients completed T1; 27/98 bereaved parents completed T1B; and 45/108 parents were interviewed. At enrolment, participants held concurrent hopes that precision medicine would benefit future children and their child. Participants expressed concern regarding wait-times for receipt of results. Most participants found the trial beneficial and not burdensome, including bereaved parents. Participants reported high trial satisfaction (median scores: parents: 93/100; patients: 80/100). Participants expressed few regrets (parent median scores: parents: 10/100; bereaved parents: 15/100; patient regret: 2/8 expressed minimal regret). CONCLUSIONS: Even when trial outcomes did not match their hopes, parents and patients rarely regretted participating in a childhood cancer precision medicine trial. These data are critical for integrating participants' views into future precision medicine delivery.
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Luto , Neoplasias , Adolescente , Criança , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão , Satisfação do Paciente , PaisRESUMO
Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.
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Subunidade alfa 2 de Fator de Ligação ao Core , Células-Tronco Hematopoéticas , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Regulação da Expressão Gênica , Hematopoese/genética , Cromatina/metabolismoRESUMO
Precision medicine programs aim to utilize novel technologies to identify personalized treatments for children with cancer. Delivering these programs requires interdisciplinary efforts, yet the many groups involved are understudied. This study explored the experiences of a broad range of professionals delivering Australia's first precision medicine trial for children with poor-prognosis cancer: the PRecISion Medicine for Children with Cancer (PRISM) national clinical trial of the Zero Childhood Cancer Program. We conducted semi-structured interviews with 85 PRISM professionals from eight professional groups, including oncologists, surgeons, clinical research associates, scientists, genetic professionals, pathologists, animal care technicians, and nurses. We analyzed interviews thematically. Professionals shared that precision medicine can add complexity to their role and result in less certain outcomes for families. Although many participants described experiencing a greater emotional impact from their work, most expressed very positive views about the impact of precision medicine on their profession and its future potential. Most reported navigating precision medicine without formal training. Each group described unique challenges involved in adapting to precision medicine in their profession. Addressing training gaps and meeting the specific needs of many professional groups involved in precision medicine will be essential to ensure the successful implementation of standard care.
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BACKGROUND: Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child's and family's future cancer risk. Understanding parents' perspectives of germline genome sequencing is critical to successful clinical implementation. METHODS: A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child's results, including clinically relevant germline findings (received by 13% of parents). Parents' expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth. RESULTS: At trial enrollment, most parents (63%) believed it was at least "somewhat likely" that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child's genome sequencing results by their child's clinician. CONCLUSIONS: Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.
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Neoplasias , Humanos , Criança , Neoplasias/genética , Neoplasias/terapia , Neoplasias/diagnóstico , Motivação , Medicina de Precisão/métodos , Pais , GenótipoRESUMO
INTRODUCTION: Identifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies indicate that 10%-15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families. METHOD AND ANALYSIS: To test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk. ETHICS AND DISSEMINATION: By evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients. TRIAL REGISTRATION NUMBER: NCT04903782.
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Neoplasias , Adolescente , Criança , Humanos , Estudos de Coortes , Suscetibilidade a Doenças , Predisposição Genética para Doença , Neoplasias/diagnóstico , Neoplasias/genética , Estudos Prospectivos , Sequenciamento Completo do Genoma/métodosRESUMO
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.
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Anormalidades Cardiovasculares , Hepatopatia Veno-Oclusiva , Adulto , Criança , Humanos , Anormalidades Cardiovasculares/complicações , Anormalidades Cardiovasculares/tratamento farmacológico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/etiologia , Incidência , Sistema de Registros , Síndrome , Transplante Homólogo/efeitos adversos , Masculino , FemininoRESUMO
AIM: To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration-time curve, AUC0â∞ ) through dosing simulations. METHODS: A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2-17.0 years) receiving three daily age-guided doses (10-14 g/m2 ). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood-ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC0â∞ values were evaluated using age, body surface area (BSA) and model-based dosing regimens, targeting 4800 mg*h/L. RESULTS: Treosulfan concentration data were described using a one-compartment PK model with first-order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9-18.1) L/h and 41.9 (38.8-45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2 years), a model-based dosing regimen more accurately achieved the target AUC0â∞ (58.3%) over the age (42.6%) and BSA-based (51.3%) regimens. CONCLUSION: Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model-informed dosing is recommended for patients under 2 years. Treosulfan PK parameters and AUC0â∞ were not influenced by patient disease.
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Bussulfano , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Lactente , Pré-Escolar , Adolescente , Estudos Prospectivos , Bussulfano/farmacocinética , Peso Corporal , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: The COVID-19 pandemic has caused major disruption to health systems, with allogeneic haemopoietic cell transplant (alloHCT) services a particularly vulnerable area. Ongoing provision of alloHCT has required dynamic responses at national and local levels. In Australia and New Zealand (ANZ), a high reliance on unrelated donors from overseas registries has posed an additional challenge. AIMS: To describe the impact of COVID-19 on alloHCT services in ANZ in the first year of the pandemic. METHODS: Data from the national alloHCT patient and unrelated donor registries were extracted for a 2-year time frame. Comparisons were made between a pre-pandemic period of 1 March 2019 to 29 February 2020 and the corresponding dates during the pandemic, 1 March 2020 to 28 February 2021. RESULTS: There was a 13% decrease in the number of allogeneic transplants, a reversal of steady increases in previous years, with the largest decrease in unrelated donor transplants. Local donors supplied a greater proportion of unrelated stem cell products. With a switch to universal cryopreservation, the time from request of a product to infusion increased by a median of 25.5 days for overseas products and 14 days for local products. There was a significant increase in the number of products collected but not used. CONCLUSIONS: A strong public health response and coordinated transplant community activities allowed for safe provision of alloHCT in ANZ; however, our data suggest that the timely delivery of allogeneic transplants was affected by the COVID-19 pandemic. Continued dedicated efforts are required to minimise further impacts.
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COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , Pandemias , Nova Zelândia/epidemiologia , COVID-19/epidemiologia , Estudos Retrospectivos , Austrália/epidemiologiaRESUMO
Patients with post-haemopoietic stem cell transplant or chimeric antigen receptor T -cell (CAR-T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally.