Sarcomas are rare and heterogeneous cancers. We assessed the contribution of DICER1 mutations to sarcoma development.
The coding region of DICER1 was sequenced in 67 sarcomas using a custom Fluidigm ...Access Array. The RNase III domains were Sanger sequenced in six additional sarcomas to identify hotspot DICER1 variants.
The median age of sarcoma diagnosis was 45.7 years (range: 3 months to 87.4 years). A recurrent embryonal rhabdomyosarcoma (ERMS) of the broad ligament, first diagnosed at age 23 years, harboured biallelic pathogenic somatic DICER1 variants (1 truncating and 1 RNase IIIb missense). We identified nine other DICER1 variants. One somatic variant (p.L1070V) identified in a pleomorphic sarcoma and one germline variant (c.2257-7A>G) may be pathogenic, but the others are considered to be benign.
We show that deleterious DICER1 mutations underlie the genetic basis of only a small fraction of sarcomas, in particular ERMS of the urogenital tract.
Germ-line
RB
-
1
mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line
DICER1
mutation in a child with a ...PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of
DICER1
mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for
DICER1
mutations; three patients were known carriers of germ-line
DICER1
mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify
DICER1
mutations in blood gDNA and/or tumour gDNA. Testing for somatic
DICER1
mutations was also conducted on one case with a known germ-line
DICER1
mutation. From the eighteen PinBs, we identified four deleterious
DICER1
mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic
DICER1
RNase IIIb mutations were identified. One PinB arising in a germ-line
DICER1
mutation carrier was found to have LOH. This study suggests that germ-line
DICER1
mutations make a clinically significant contribution to PinB, establishing
DICER1
as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line
DICER1
mutation. The means by which the second allele is inactivated may differ from other
DICER1
-related tumours.
Adolescent and young adult (AYA) survivors of pediatric oncology related cerebral insult are vulnerable to numerous treatment-induced deficits that significantly enhance cardiovascular disease risk. ...Regular exercise improves endothelial function, fitness, body composition and musculoskeletal function which may reduce predisposition for cardiovascular disease. Here we assessed the feasibility and effectiveness of a 24-week exercise intervention on cardiovascular, physical and metabolic outcomes in this population. Thirteen survivors (6 male, 7 female; median age 19 y (range 16-23 y) were recruited to participate in a 48-week study consisting of a 24-week control period (regular care) followed by a 24-week exercise intervention. Outcome measures were collected at entry (week 0) and following regular care (24-week) and exercise (48-week). Assessed variables included endothelial function (flow mediated dilation, FMD), blood pressure, heart rate (HR), aerobic capacity, anthropometry, body composition, muscular strength (3 repetition maximum testing), muscular endurance (repetitions/min) and physical activity levels (accelerometry). Compared to baseline, delta diameter (p = 0.008) and FMD (p = 0.029) of the brachial artery increased following exercise. Bicep-curl strength also increased following exercise compared to baseline (p = 0.019), while submaximal (6 min mark) measures of ventilation (p = 0.012), rating of perceived exertion (p = 0.012), HR (p = 0.001), absolute (p = 0.000) and relative (p = 0.000) aerobic capacity decreased. Breaks in sedentary time increased (p = 0.043) following exercise compared to regular care. Although the sample was small and heterogeneous, this study demonstrates that exercise is achievable and has positive effects on vascular function, submaximal fitness, local strength and physical activity in a population of AYA survivors of pediatric oncology related cerebral insult.
The EQ-5D-Y-5L is a generic preference-based measure of health-related quality of life for children. This study aimed to describe the distributional properties, test-retest reliability, and ...convergent validity of the EQ-5D-Y-5L in children with intellectual disability (ID).
Caregivers of children with ID (aged 4 to 18 years) completed an online survey, including a proxy-report EQ-5D-Y-5L, the Quality-of-life Inventory-Disability, and disability-appropriate measures corresponding to the EQ-5D dimensions: mobility, self-care (SC), usual activities (UA), pain/discomfort (PD), and worry/sadness/unhappiness. Twenty-one participants repeated the EQ-5D-Y-5L a few weeks later. Test-retest reliability was computed using weighted kappa and intraclass correlation coefficients, and convergent validity using Spearman’s and Pearson’s correlation coefficients.
Caregivers of 234 children completed the survey, with <1% missing values. Only 1.7% reported “no problems” on all dimensions (11111). The dimensions with the lowest percentage of “no problems” were SC and UA (both 8%). Test-retest reliability coefficients were fair to substantial for 4 dimensions (weighted kappa .30 to .79) but low for PD and overall health, as measured by the visual analog scale (EQ-VAS). Convergent validity was strong (Spearman’s correlation .65 to .87) for mobility, SC, and PD; moderate to strong for worry/sadness/unhappiness (.47 to .60) and the EQ-VAS (Pearson’s correlation .49); and weak to moderate for UA (.21 to .52).
Convergent validity was generally good; test-retest reliability varied. Children with ID had lower scores on SC and UA than other populations, and their EQ-VAS could fluctuate greatly, indicating poorer and less stable health-related quality of life.
•The EQ-5D is a health-related quality-of-life scale, with established psychometric properties across diverse adult and child populations. It can generate utility values, translatable into quality-adjusted life years, which are used to value health in economic analyses.•A caregiver-completed proxy version of the EQ-5D-Y-5L, when applied to children with intellectual disability (ID), has good distributional properties with extremely few (<1%) missing values and without ceiling effects. Compared with other populations, children with ID score poorly on self-care, usual activities, and worry/sadness/unhappiness. Convergent validity is good for most dimensions and for the EQ-VAS. Test-retest reliability is fair to substantial for 4 dimensions but poor for pain/discomfort and EQ-VAS, indicating variable health states in some children.•Although ID is not a disease state, these children’s EQ-5D-Y-5L scores indicate severe problems affecting health-related quality-of-life compared with most other populations, particularly in regard to the self-care, usual activities, and worry/sadness/unhappiness dimensions. The data may inform policy makers and decision makers to allow comparison of costs and benefits across healthcare and the disability sectors. The EQ-VAS is not stable and could not be used to monitor changes with intervention over time.
The EQ-5D-5L is a generic health utility instrument for measuring health-related quality of life (HRQoL), with self-report and proxy report versions for children (EQ-5D-Y-5L). Children with ...intellectual disability (ID) are a heterogeneous population whose impairments and comorbidities place them at risk of poor HRQoL. This study aimed to describe the content validity and suitability for children with ID of a proxy report version of the EQ-5D-Y-5L as seen by their caregivers.
A proxy report EQ-5D-Y-5L was administered to caregivers of children with ID. Using cognitive think-aloud interviewing, participants were encouraged to provide the reasoning for their choices, assess the questions’ relevance, comprehensibility, and comprehensiveness, and comment on the tool’s strengths and weaknesses. Qualitative content analysis used both directed (deductive) and conventional (inductive) methods.
There were 28 interviews with 30 caregivers of children with ID (aged 8-22 years, 17 boys, with autism spectrum disorder, cerebral palsy, Down syndrome, and rare genetic disorders). The EQ-5D-Y-5L was considered clear, concise, and largely relevant, but insufficiently comprehensive for this population. Interviewees sought clarification of the definition of HRQoL, whether it included unchanging impairments (vs fluctuating health states), and what basis of comparison to use (child or peer). Many interviewees suggested inclusion of questions for other domains, including communication and social engagement, equipment and human supports required, and a wider range of mental health questions.
The study suggests that further work is required to ensure accurate responses to the EQ-5D-Y-5L from caregivers of children with ID and to describe these children adequately.
•The EQ-5D is a widely used scale for measuring health-related quality of life, with established reliability and validity in a diversity of adult and pediatric populations. It is used to assign economic value to changes in health status.•Use of the EQ-5D-Y-5L presents challenges for carers of children with intellectual disability (ID), particularly in regard to the influence of unchanging impairments, variable expectations for children with ID compared with typically developing children, the omission of questions about supports required by children, and difficulties for parents reporting on behalf of their children, particularly about pain.•Healthcare decision making, if based on a current version of the EQ-5D-Y-5L, is likely to overestimate health-related quality of life in children with ID, because most caregivers assume the availability of support (person or equipment or both) when answering the questions and because expectations for children with ID are different from expectations of neurotypical children and answers are adjusted to take into account these limitations. Comparison of EQ-5D-Y-5L results between children with ID and neurotypical children may be invalid.
Objective:
We examined the impact of long-term mental health outcomes on healthcare services utilisation among childhood cancer survivors in Western Australia using linked hospitalisations and ...community-based mental healthcare records from 1987 to 2019.
Method:
The study cohort included 2977 childhood cancer survivors diagnosed with cancer at age < 18 years in Western Australia from 1982 to 2014 and a matched non-cancer control group of 24,994 individuals. Adjusted hazard ratios of recurrent events were estimated using the Andersen–Gill model. The cumulative burden of events over time was assessed using the method of mean cumulative count. The annual percentage change in events was estimated using the negative binomial regression model.
Results:
The results showed higher community-based service contacts (rate/100 person-years: 30.2, 95% confidence interval = 29.7–30.7 vs 22.8, 95% confidence interval = 22.6–22.9) and hospitalisations (rate/1000 person-years: 14.8, 95% confidence interval = 13.6–16.0 vs 12.7, 95% confidence interval = 12.3–13.1) in childhood cancer survivors compared to the control group. Childhood cancer survivors had a significantly higher risk of any event (adjusted hazard ratio = 1.5, 95% confidence interval = 1.1–2.0). The cumulative burden of events increased with time since diagnosis and across age groups. The annual percentage change for hospitalisations and service contacts significantly increased over time (p < 0.05). Substance abuse was the leading cause of hospitalisations, while mood/affective and anxiety disorders were common causes of service contacts. Risk factors associated with increased service events included cancer diagnosis at age < 5 years, leukaemia diagnosis, high socioeconomic deprivation, and an attained age of < 18 years.
Conclusions:
The elevated utilisation of healthcare services observed among childhood cancer survivors emphasises the need for periodic assessment of psychiatric disorders, particularly in high-risk survivors, to facilitate early management and optimise healthcare resources.
Aim
Hyponatraemia with hyperkalaemia in infancy is a typical presentation of congenital adrenal hyperplasia. In the presence of pyelonephritis, the same biochemical picture can occur with transient ...type 1 pseudohypoaldosteronism (PHA‐1) also termed type 4 renal tubular acidosis. Recognition of PHA‐1 enables appropriate management thus avoiding unnecessary investigations and treatment. To improve awareness of this condition, we present a case series to highlight the clinical and biochemical features of PHA‐1.
Methods
A retrospective chart review of patients diagnosed with transient PHA‐1 at a tertiary children's hospital in Western Australia was conducted.
Results
Five male infants (32 days to 6 months) with transient PHA‐1 were identified. Failure to thrive was the most common symptom with hyponatraemia on presentation. Two infants had antenatally diagnosed bilateral hydronephrosis and urinary tract infection (UTI) on admission. Two infants were treated for congenital adrenal hyperplasia and received hydrocortisone. All infants had UTI and required parenteral antibiotics. The condition was transient and hyponatraemia corrected by day 4 in all infants. There was no correlation between plasma sodium and aldosterone levels. The severity of PHA‐1 was independent of the underlying renal anomaly. Four infants had hydronephrosis and vesicoureteric reflux. Surgical intervention was required in two infants.
Conclusions
PHA‐1 may be precipitated by UTI or urinary tract anomalies in early infancy. Urine analysis should be performed in infants with hyponatraemia. Diagnosis of PHA‐1 facilitates appropriate renal investigations to reduce long‐term morbidity.
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