| 1. |
- Holst, Anders, et al.
(författare)
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Identifying causal relationships of cancer treatment and long-term health effects among 5-year survivors of childhood cancer in Southern Sweden
- 2022
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Ingår i: Communications medicine. - : Springer Science and Business Media LLC. - 2730-664X. ; 2, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of childhood cancer can develop adverse health events later in life. Infrequent occurrences and scarcity of structured information result in analytical and statistical challenges. Alternative statistical approaches are required to investigate the basis of late effects in smaller data sets.Methods: Here we describe sex-specific health care use, mortality and causal associations between primary diagnosis, treatment and outcomes in a small cohort ( n = 2315) of 5-year survivors of childhood cancer ( n = 2129) in southern Sweden and a control group ( n = 11,882; age-, sex- and region-matched from the general population). We developed a constraint-based method for causal inference based on Bayesian estimation of distributions, and used it to investigate health care use and causal associations between diagnoses, treatments and outcomes. Mortality was analyzed by the Kaplan-Meier method. Results: Our results confirm a significantly higher health care usage and premature mortality among childhood cancer survivors as compared to controls. The developed method for causal inference identifies 98 significant associations ( p < 0.0001) where most are well known ( n = 73; 74.5%). Hitherto undescribed associations are identified ( n = 5; 5.1%). These were between use of alkylating agents and eye conditions, topoisomerase inhibitors and viral infections; pituitary surgery and intestinal infections; and cervical cancer and endometritis. We discuss study-related biases ( n = 20; 20.4%) and limitations. Conclusions: The findings contribute to a broader understanding of the consequences of cancer treatment. The study shows relevance for small data sets and causal inference, and presents the method as a complement to traditional statistical approaches.
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| 2. |
- Broberg, Olof, et al.
(författare)
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Ceramides : a potential cardiovascular biomarker in young adult childhood cancer survivors?
- 2024
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Ingår i: European Heart Journal Open. - 2752-4191. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Aims The aim of this study was to investigate circulating ceramides involved in cardiovascular disease (CVD) in young adult childhood cancer survivors (CCS) and their correlations to previously reported adverse cardiovascular changes in this cohort. Methods Fifty-seven CCS and 53 healthy controls (age 20-30 years) were studied. Plasma long-chain ceramides, known to be cardi- and results otoxic (C16:0, C18:0, C24:0, and C24:1), were analysed by mass spectrometry. The coronary event risk test 2 (CERT2) score was calculated from the ceramide data. Cardiac and carotid artery ultrasound data and lipid data available from previous studies of this cohort were used to study partial correlations with ceramide and CERT2 score data. All four analysed ceramides were elevated in CCS compared with controls (P ≤ 0.012). The greatest difference was noted for C18:0, which was 33% higher in CCS compared with controls adjusted for sex, age, and body mass index (BMI) (P < 0.001). The CERT2 score was higher in CCS compared with controls (P < 0.001). In the CCS group, 35% had a high to very high CERT2 score (7-12) when compared with 9% in the control group (P < 0.001). The CCS subgroup with a CERT2 score ≥ 7 had higher heart rate, systolic blood pressure, and higher levels of apolipoprotein B compared with CCS with a CERT2 score < 6 (P ≤ 0.011). When adjusted for age, sex, and BMI, CERT2 score was significantly correlated with arterial stiffness, growth hormone, and cranial radiotherapy (P < 0.044). Conclusion Ceramides could be important biomarkers in understanding the pathophysiology of CVD and in predicting CVD disease risk in young adult CCS.
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| 3. |
- Broberg, Olof, et al.
(författare)
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Characterization of Cardiac, Vascular, and Metabolic Changes in Young Childhood Cancer Survivors
- 2021
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Ingår i: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer survivors (CCS) are at an increased risk for cardiovascular diseases (CVD). It was the primary aim of this study to determine different measures of cardiac, carotid, lipid, and apolipoprotein status in young adult CCS and in healthy controls. Methods: Cardiac and common carotid artery (CCA) structure and function were measured by ultrasonography. Lipids and apolipoproteins were measured in the blood. Peripheral arterial endothelial vasomotor function was assessed by measuring digital reactive hyperemia index (PAT-RHI) using the Endo-PAT 2000. Results: Fifty-three CCS (20-30 years, 35 men) and 53 sex-matched controls were studied. The CCS cohort was divided by the median dose of anthracyclines into a low anthracycline dose (LAD) group (50-197 mg/m2, n = 26) and a high anthracycline dose (HAD) group (200-486 mg/m2, n = 27). Carotid distensibility index (DI) and endothelial function determined by PAT-RHI were both lower in the CCS groups compared with controls (p < 0.05 and p = 0.02). There was no difference in carotid intima media thickness. Atherogenic apolipoprotein-B (Apo-B) and the ratio between Apo-B and Apoliprotein-A1 (Apo-A1) were higher in the HAD group compared with controls (p < 0.01). Apo-B/Apo-A1-ratio was over reference limit in 29.6% of the HAD group, in 15.4% of LAD group, and in 7.5% of controls (p = 0.03). Measured lipid markers (low density lipoprotein and total cholesterol and triglycerides) were higher in both CCS groups compared with controls (p < 0.05). Systolic and diastolic function were measurably decreased in the HAD group, as evidenced by lower EF (p < 0.001) and lower é-wave (p < 0.005) compared with controls. CCA DI correlated with Apo-B/Apo-A1-ratio and Apo-A1. Follow-up time after treatment correlated with decreased left ventricular ejection fraction (p = 0.001). Conclusion: Young asymptomatic CCS exhibit cardiac, vascular, lipid, and apolipoprotein changes that could account for increased risk for CVD later in life. These findings emphasize the importance of cardiometabolic monitoring even in young CCS.
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| 4. |
- Broberg, Olof, et al.
(författare)
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Childhood Cancer Survivors Have Impaired Strain-Derived Myocardial Contractile Reserve by Dobutamine Stress Echocardiography
- 2023
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Ingår i: Journal of Clinical Medicine. - 2077-0383. ; 12:8, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal left ventricular contractile reserve (LVCR) is associated with adverse cardiac outcomes in different patient cohorts and might be useful in the detection of cardiomyopathy in childhood cancer survivors (CCS) after cardiotoxic treatment. The aim of this study was to evaluate LVCR by dobutamine stress echocardiography (DSE) combined with measures of myocardial strain in CCS previously treated with anthracyclines (AC). Fifty-three CCS (age 25.34 ± 2.44 years, 35 male) and 53 healthy controls (age 24.40 ± 2.40 years, 32 male) were included. Subjects were examined with echocardiography at rest, at low-dose (5 micrograms/kg/min), and at high-dose (40 micrograms/kg/min) dobutamine infusion. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), strain rate (GSR), and early diastolic strain rate (GEDSR) at different DSE phases were used as measures of LVCR. The mean follow-up time among CCS was 15.8 ± 5.8 years. GLS, GSR, and LVEF were lower at rest in CCS compared to controls (p ≤ 0.03). LVEF was within the normal range in CCS. ΔGLS, ΔGSR, and ΔGEDSR but not ΔLVEF were lower in CCS compared to controls after both low- (p ≤ 0.048) and high-dose dobutamine infusion (p ≤ 0.023). We conclude that strain measures during low-dose DSE detect impaired myocardial contractile reserve in young CCS treated with AC at 15-year follow-up. Thus, DSE may help identify asymptomatic CCS at risk for heart failure and allows for tailored follow-up accordingly.
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| 5. |
- Broberg, Olof, et al.
(författare)
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Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer
- 2024
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Ingår i: Cardiology in the Young. - 1047-9511 .- 1467-1107.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease.METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index).RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005).CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.
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| 6. |
- Fisher, Jane, et al.
(författare)
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The Dynamics of Circulating Heparin-Binding Protein : Implications for Its Use as a Biomarker
- 2022
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 14:5, s. 447-460
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Tidskriftsartikel (refereegranskat)abstract
- Heparin-binding protein (HBP) is a promising biomarker for the development and severity of sepsis. To guide its use, it is important to understand the factors that could lead to false-positive or negative results, such as inappropriate release and inadequate clearance of HBP. HBP is presumably released only by neutrophils, and the organs responsible for its elimination are unknown. In this study, we aimed to determine whether non-neutrophil cells can be a source of circulating HBP and which organs are responsible for its removal. We found that in two cohorts of neutropenic patients, 12% and 19% of patients in each cohort, respectively, had detectable plasma HBP levels. In vitro, three leukemia-derived monocytic cell lines and healthy CD14+ monocytes constitutively released detectable levels of HBP. When HBP was injected intravenously in rats, we found that plasma levels of HBP decreased rapidly, with a distribution half-life below 10 min and an elimination half-life of 1-2 h. We measured HBP levels in the liver, spleen, kidneys, lungs, and urine using both ELISA and immunofluorescence quantitation, and found that the majority of HBP was present in the liver, and a small amount was present in the spleen. Immunofluorescence imaging indicated that HBP is associated mainly with hepatocytes in the liver and monocytes/macrophages in the spleen. The impact of hematologic malignancies and liver diseases on plasma HBP levels should be explored further in clinical studies.
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| 7. |
- Heymer, Emma J., et al.
(författare)
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Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe : the PanCareSurFup study
- 2024
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Ingår i: British Journal of Cancer. - 0007-0920. ; 130:6, s. 976-986
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. Methods: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940–2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. Results: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. Discussion: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.
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| 8. |
- Reulen, Raoul C, et al.
(författare)
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Risk Factors for Primary Bone Cancer After Childhood Cancer : A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study
- 2023
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 41:21, s. 3735-3746
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy.METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship.RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( P trend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m 2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m 2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.
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| 9. |
- Reulen, RC, et al.
(författare)
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Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study
- 2021
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70:8, s. 1520-1528
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Tidskriftsartikel (refereegranskat)abstract
- Survivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide.MethodsThe PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence.Results427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN—comparable to the risk among members of the general population with at least two first-degree relatives affected.ConclusionsColonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.
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| 10. |
- Stjernfelt, Karl-Johan, et al.
(författare)
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Increased cancer risk in families with pediatric cancer is associated with gender, age, diagnosis, and degree of relation to the child
- 2020
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 29:11, s. 2171-2179
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies of cancer risk among relatives of children with cancer beyond parents and siblings are limited. We have investigated the cancer risk up to the third degree of relation in families with pediatric cancer to reveal patterns of inheritance.METHODS: A single-center cohort of 757 pediatric cancer patients was linked to the Swedish National Population Register, resulting in 16 137 relatives up to the third degree of relation. All relatives were matched to the Swedish Cancer Register and standard incidence ratios (SIRs) were calculated to define relatives at risk.RESULTS: Children and adults up to the third degree of relation had increased cancer risk, with SIRs of 1.48 (P=0.01) and 1.07 (P<0.01), respectively. The SIRs for first- and third-degree adult relatives were 1.22 and 1.10, respectively, but no increased risk was observed in second-degree relatives. Male relatives had a higher risk than females, especially when related to a girl and when the child had leukemia. The risk was mainly increased for lung, prostate and gastrointestinal cancer. When excluding 29 families of children with known pathogenic germline variants, the increased risk remained.CONCLUSION: Relatives to children with cancer up to third degree of relation have an increased cancer risk. Known pathogenic germline variants do not explain this increased risk.IMPACT: The overall increased cancer risk among relatives of children with cancer in this population-based cohort strengthens the importance of surveillance programs for families with pediatric cancer.
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