Offspring of childhood cancer survivors may be at risk of genetic disease due to the mutagenic cancer treatments received by their parents. Congenital malformations were evaluated in a ...population‐based cohort study of 1715 offspring of 3963 childhood cancer survivors and 6009 offspring of 5657 survivors’ siblings. The Danish Central Population Register, Cancer Registry and Hospital Register were used to identify study subjects and congenital malformations. Gonadal and uterine radiation doses were characterized based on standard radiation‐treatment regimens. The prevalence of congenital malformations at birth in offspring of survivors (44 cases, 2.6%) was slightly higher but not statistically different from that of offspring of siblings (140 cases, 2.3%) prevalence proportion ratio (PPR), 1.1; 95% confidence interval, 0.8–1.5 or of the general population (observed‐to‐expected ratio, 1.2; 0.9–1.6). Including malformations diagnosed later in life did not change the ratios appreciably. The risk for malformations was slightly higher in the offspring of irradiated parents than in that of non‐irradiated parents (PPR 1.2 vs 1.0) but was unrelated to gonadal dose. This study provides evidence that cancer therapy of children does not increase the risk for malformations in their offspring. Continued monitoring of genetic risks among their offspring, however, is warranted.
Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X receptor (LXR) transcription factors are important ...determinants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid metabolism. However, their role in governing the composition of lipid species such as lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the lipidome of bone marrow–derived macrophages (BMDMs) following LXR activation. We found a marked reduction in the levels of lysoplasmalogen species in the absence of changes in the levels of plasmalogens themselves. Transcriptional profiling of LXR-activated macrophages identified the gene encoding transmembrane protein 86a (TMEM86a), an integral endoplasmic reticulum protein, as a previously uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct transcriptional target of LXR in macrophages and microglia and that it is highly expressed in TREM2+/lipid-associated macrophages in human atherosclerotic plaques, where its expression positively correlates with other LXR-regulated genes. We further show that both murine and human TMEM86a display active lysoplasmalogenase activity that can be abrogated by inactivating mutations in the predicted catalytic site. Consequently, we demonstrate that overexpression of Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels and abrogates the LXR-dependent reduction of this lipid species. Collectively, our findings implicate TMEM86a as a sterol-regulated lysoplasmalogenase in macrophages that contributes to sterol-dependent membrane remodeling.
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Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes ...related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10
) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m
: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for ...adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (-2.9; 95% confidence interval = -4.0 to -1.7) compared to AYAs (-1.8; -2.1 to -1.5) and adults aged >40 years (-1.5; -1.6 to -1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children -4.6 (-6.1 to -3.1) vs AYAs -3.2 (-4.2 to -2.1) and over 40s -1.1 (-1.3 to -0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients.
Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and ...young adulthood (CAYA) cancer survivors?
Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively.
Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce.
The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study.
All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites.
A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively.
Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results.
We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired.
This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests.
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ABSTRACT
Asteroseismology is a powerful tool to infer fundamental stellar properties. The use of these asteroseismic-inferred properties in a growing number of astrophysical contexts makes it vital ...to understand their accuracy. Consequently, we performed a hare-and-hounds exercise where the hares simulated data for six artificial main-sequence stars and the hounds inferred their properties based on different inference procedures. To mimic a pipeline such as that planned for the PLATO mission, all hounds used the same model grid. Some stars were simulated using the physics adopted in the grid, others a different one. The maximum relative differences found (in absolute value) between the inferred and true values of the mass, radius, and age were 4.32, 1.33, and 11.25 per cent, respectively. The largest systematic differences in radius and age were found for a star simulated assuming gravitational settling, not accounted for in the model grid, with biases of −0.88 per cent (radius) and 8.66 per cent (age). For the mass, the most significant bias (−3.16 per cent) was found for a star with a helium enrichment ratio outside the grid range. Moreover, an ∼7 per cent dispersion in age was found when adopting different prescriptions for the surface corrections or shifting the classical observations by ±1σ. The choice of the relative weight given to the classical and seismic constraints also impacted significantly the accuracy and precision of the results. Interestingly, only a few frequencies were required to achieve accurate results on the mass and radius. For the age the same was true when at least one l = 2 mode was considered.
Background
Neurological prognostication is an essential part of post‐resuscitation care in out‐of‐hospital cardiac arrest (OHCA). This study aims to assess the use of computed tomography (CT) and ...magnetic resonance imaging (MR) of the head, electroencephalography (EEG), and somatosensory evoked potentials (SSEP) in neurological prognostication in resuscitated OHCA patients and factors associated with their use in Danish tertiary and non‐tertiary centers from 2005 to 2013 and associations with outcome.
Methods
We used the Danish Cardiac Arrest Registry to identify patients ≥18 years of age admitted to intensive care units due to OHCA of presumed cardiac etiology. CT 0‐20 days and MR, SSEP, and EEG ≥2‐20 days post OHCA were considered related to prognostication. Incidence and factors associated with procedures were assessed by multiple Cox regression with death as competing risk.
Results
Use of CT, MR, EEG, and SSEP increased during the study period (CT: 51%‐67%, HRCT: 1.06, CI: 1.03‐1.08, MR: 2%‐5%, P = .08, EEG: 6%‐33%, HREEG: 1.25, CI: 1.19‐1.30, SSEP: 4%‐15%, HRSSEP: 1.23, CI: 1.15‐1.32). EEG and SSEP were more used in tertiary centers than non‐tertiary (HREEG: 1.86, CI: 1.51‐2.29, HRSSEP: 4.44, CI: 2.86‐6.89). Use of CT, SSEP, and EEG were associated with higher 30‐day mortality, and MR was associated with lower (HRCT: 1.15, CI: 1.01‐1.30, HRMR: 0.53, CI: 0.37‐0.77, HRSSEP: 1.90, CI: 1.57‐2.32, HREEG: 1.75, CI: 1.49‐2.05).
Conclusion
Use of neurological prognostication procedures increased during the study period. EEG and SSEP were more used in tertiary centers. CT, EEG and SSEP were associated with increased mortality.
Abstract Aim Childhood cancer survivors are at risk of both somatic and mental late effects, but large population-based studies of depression are lacking. Methods Risk of antidepressant use was ...evaluated in a population-based cohort of 5452 Danish children treated for cancer in 1975–2009 by linkage to the National Prescription Drug Database, which worldwide is the oldest nationwide registry of prescription medication. Hazard ratios (HRs) for antidepressant use were estimated in a Cox proportional hazards model stratified on sex, with population comparisons as referents. Results Overall, childhood cancer survivors were at increased risk of having antidepressants prescribed (HR, 1.4; 95% confidence interval (CI), 1.3–1.5). The excess absolute risk of antidepressant use was 2.5 per 1000 person-years (95% CI, 1.7–3.3), equivalent to an excess of 2.5 survivors for every 100 survivors followed for 10 years. Increased HRs of 30–50% were seen for survivors of cancers of all main groups (haematological malignancies, central nervous system (CNS) and solid tumors); the highest risk was among children treated with haematopoietic stem cell transplantation (HR, 1.9; 95% CI, 1.2–3.1). Our data suggested that the risk was most pronounced for children treated in the most recent calendar periods (test for interaction between cancer and calendar periods: P < 0.001), especially for survivors of haematological cancers ( P = 0.007). Interaction analysis of the effect of parental socioeconomic position and psychiatric disease on the association between childhood cancer and antidepressant use indicated no modifying effect. Conclusion Childhood cancer survivors should be followed-up for depression. Our results indicate an increasing need for follow-up especially in survivors treated by more recent, intensive anticancer treatment.
To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases.
This was a population-based study in the five ...Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk.
The overall SMR was 10.8 (95% confidence interval CI, 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment.
Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.
Pregnancy-associated cancer (PAC) is increasing over time in many countries. We provide a comprehensive, population-based overview of cancer survival in women with PAC across five decades.
We ...performed a nationwide cohort study of 121,382 women diagnosed with cancer at age 15–49 between 1970 and 2018 using birth and cancer registers in Sweden. Pregnancy-associated cancer was defined as diagnosed during pregnancy and within one year of delivery, while non-PAC was outside this window. Cox regression estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing cancer mortality for PAC versus non-PAC.
In total, 5079 women had a diagnosis of PAC. Cutaneous malignant melanoma, breast, cervical, thyroid and central nervous system (CNS) were the most common sites of PAC. A higher cancer mortality was observed in PAC versus non-PAC for breast (HR = 1.72, 95% CI 1.54–1.93) and uterine cancer (myometrium/unspecified) (8.62, 2.80–26.53), in which all PAC deaths were uterine sarcomas. Increased mortality was also observed in upper digestive tract cancer diagnosed during pregnancy and colon cancer diagnosed during first year after delivery. Contrary, the HR for CNS tumours was significantly decreased (0.71, 0.55–0.91). Survival after PAC improved for most sites over time, with survival after breast cancer during pregnancy in recent years being similar to that of non-pregnancy associated breast cancer.
For the majority of sites, PAC was not associated with poorer prognosis compared to non-PAC, a finding which was stable over time. The main exceptions were breast cancer and rarer cancers, such as uterine sarcoma.
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•Pregnancy-associated cancer (PAC) is rare but increasing in many countries.•This is the first population-based overview including survival for all sites.•PAC was generally not associated with a worse cancer survival than non-PAC.•Time trends revealed improved PAC survival over time in level with non-PAC.
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