Background: Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce,... Show moreBackground: Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce, especially in European survivors. The aim of this cross-sectional study was to assess the prevalence of and explore risk factors for pre-frailty, frailty, and sarcopenia in a national cohort of Dutch childhood cancer survivors diagnosed between 1963 and 2001.Methods: Eligible individuals (alive at the time of study, living in the Netherlands, age 18-45 years, and had not previously declined to participate in a late-effects study) from the Dutch Childhood Cancer Survivor Study (DCCSS-LATER) cohort were invited to take part in this cross-sectional study. We defined pre-frailty and frailty according to modified Fried criteria, and sarcopenia according to the European Working Group on Sarcopenia in Older People 2 definition. Associations between these conditions and demographic and treatment-related as well as endocrine and lifestyle-related factors were estimated with two separate multivariable logistic regression models in survivors with any frailty measurement or complete sarcopenia measurements. Findings: 3996 adult survivors of the DCCSS-LATER cohort were invited to participate in this cross-sectional study. 1993 non-participants were excluded due to lack of response or a decline to participate and 2003 (50.1%) childhood cancer survivors aged 18-45 years were included. 1114 (55.6%) participants had complete frailty measurements and 1472 (73.5%) participants had complete sarcopenia measurements. Mean age at participation was 33.1 years (SD 7.2). 1037 (51.8%) participants were male, 966 (48.2%) were female, and none were transgender. In survivors with complete frailty measurements or complete sarcopenia measurements, the percentage of pre-frailty was 20.3% (95% CI 18.0-22.7), frailty was 7.4% (6.0-9.0), and sarcopenia was 4.4% (3.5-5.6). In the models for pre-frailty, underweight (odds ratio [OR] 3.38 [95% CI 1.92-5.95]) and obesity (OR 1.67 [1.14-2.43]), cranial irradiation (OR 2.07 [1.47-2.93]), total body irradiation (OR 3.17 [1.77-5.70]), cisplatin dose of at least 600 mg/m2 (OR 3.75 [1.82-7.74]), growth hormone deficiency (OR 2.25 [1.23-4.09]), hyperthyroidism (OR 3.72 [1.63-8.47]), bone mineral density (Z score <=-1 and >-2, OR 1.80 [95% CI 1.31-2.47]; Z score <=-2, OR 3.37 [2.20-5.15]), and folic acid deficiency (OR 1.87 [1.31-2.68]) were considered significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR 1.94 [95% CI 1.19-3.16]), underweight (OR 3.09 [1.42-6.69]), cranial irradiation (OR 2.65 [1.59-4.34]), total body irradiation (OR 3.28 [1.48-7.28]), cisplatin dose of at least 600 mg/m2 (OR 3.93 [1.45-10.67]), higher carboplatin doses (per g/m2; OR 1.15 [1.02-1.31]), cyclophosphamide equivalent dose of at least 20 g/m2 (OR 3.90 [1.65-9.24]), hyperthyroidism (OR 2.87 [1.06-7.76]), bone mineral density Z score <=-2 (OR 2.85 [1.54-5.29]), and folic acid deficiency (OR 2.04 [1.20-3.46]). Male sex (OR 4.56 [95%CI 2.26-9.17]), lower BMI (continuous, OR 0.52 [0.45-0.60]), cranial irradiation (OR 3.87 [1.80-8.31]), total body irradiation (OR 4.52 [1.67-12.20]), hypogonadism (OR 3.96 [1.40-11.18]), growth hormone deficiency (OR 4.66 [1.44-15.15]), and vitamin B12 deficiency (OR 6.26 [2.17-1.81]) were significantly associated with sarcopenia. Interpretation: Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors. Early recognition and interventions for endocrine disorders and dietary deficiencies could be important in minimising the risk of pre-frailty, frailty, and sarcopenia in this population. Copyright (C) 2023 The Author(s). Published by Elsevier Ltd. Show less
Hudson, J.; Cruickshank, M.; Quinton, R.; Aucott, L.; Aceves-Martins, M.; Gillies, K.; ... ; Jayasena, C.N. 2022
Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most... Show moreBackground: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9.5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0.4%] of 1621) than placebo (12 [0.8%] of 1537) without significant differences between groups (odds ratio [OR] 0.46 [ 95% CI 0.17-1.24]; p=0.13). Cardiovascular risk was similar during testosterone treatment (120 [7.5%] of 1601 events) and placebo treatment (110 [7.2%] of 1519 events; OR 1.07 [95% CI 0.81-1.42]; p=0. 62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0.97 [99% CI 0.92- 1.03]; p=0.17), baseline testosterone (interaction 0.97 [0 .82-1.15]; p=0.69), smoking status (interaction 1.68 [0.41-6.88]; p=0.35), or diabetes status (interaction 2.08 [0.89-4.82; p=0.025) were not associated with cardiovascular risk .Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. Show less
Plas-Krijgsman, W.G. van der; Giardiello, D.; Putter, H.; Steyerberg, E.W.; Bastiaannet, E.; Stiggelbout, A.M.; ... ; Glas, N.A. de 2021
Background Current prediction tools for breast cancer outcomes are not tailored to the older patient, in whom competing risk strongly influences treatment effects. We aimed to develop and validate... Show moreBackground Current prediction tools for breast cancer outcomes are not tailored to the older patient, in whom competing risk strongly influences treatment effects. We aimed to develop and validate a prediction tool for 5-year recurrence, overall mortality, and other-cause mortality for older patients (aged >= 65 years) with early invasive breast cancer and to estimate individualised expected benefits of adjuvant systemic treatment.Methods We selected surgically treated patients with early invasive breast cancer (stage I-III) aged 65 years or older from the population-based FOCUS cohort in the Netherlands. We developed prediction models for 5-year recurrence, overall mortality, and other-cause mortality using cause-specific Cox proportional hazard models. External validation was performed in a Dutch Cancer registry cohort. Performance was evaluated with discrimination accuracy and calibration plots.Findings We included 2744 female patients in the development cohort and 13631 female patients in the validation cohort. Median age was 74.8 years (range 65-98) in the development cohort and 76.0 years (70-101) in the validation cohort. 5-year follow-up was complete for more than 99% of all patients. We observed 343 and 1462 recurrences, and 831 and 3594 deaths, of which 586 and 2565 were without recurrence, in the development and validation cohort, respectively. The area under the receiver-operating-characteristic curve at 5 years in the external dataset was 0.76 (95% CI 0.75-0.76) for overall mortality, 0.76 (0.76-0.77) for recurrence, and 0.75 (0.74-0.75) for other-cause mortality.Interpretation The PORTRET tool can accurately predict 5-year recurrence, overall mortality, and other-cause mortality in older patients with breast cancer. The tool can support shared decision making, especially since it provides individualised estimated benefits of adjuvant treatment. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Sablerolles, R.S.G.; Lafeber, M.; Kempen, J.A.L. van; Loo, B.P.A. van de; Boersma, E.; Rietdijk, W.J.R.; ... ; COMET Res Team 2021
Background During the COVID-19 pandemic, the scarcity of resources has necessitated triage of critical care for patients with the disease. In patients aged 65 years and older, triage decisions are... Show moreBackground During the COVID-19 pandemic, the scarcity of resources has necessitated triage of critical care for patients with the disease. In patients aged 65 years and older, triage decisions are regularly based on degree of frailty measured by the Clinical Frailty Scale (CFS). However, the CFS could also be useful in patients younger than 65 years. We aimed to examine the association between CFS score and hospital mortality and between CFS score and admission to intensive care in adult patients of all ages with COVID-19 across Europe.Methods This analysis was part of the COVID Medication (COMET) study, an international, multicentre, retrospective observational cohort study in 63 hospitals in 11 countries in Europe. Eligible patients were aged 18 years and older, had been admitted to hospital, and either tested positive by PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or were judged to have a high clinical likelihood of having SARS-CoV-2 infection by the local COVID-19 expert team. CFS was used to assess level of frailty: fit (CFS1-3), mildly frail (CFS4-5), or frail (CFS6-9). The primary outcome was hospital mortality. The secondary outcome was admission to intensive care. Data were analysed using a multivariable binary logistic regression model adjusted for covariates (age, sex, number of drugs prescribed, and type of drug class as a proxy for comorbidities).Findings Between March 30 and July 15, 2020, 2434 patients (median age 68 years [IQR(55-77)]; 1480 [61%] men, 954 [30%] women) had CFS scores available and were included in the analyses. In the total sample and in patients aged 65 years and older, frail patients and mildly frail patients had a significantly higher risk of hospital mortality than fit patients (total sample: CFS6-9 vs CFS1-3 odds ratio [OR] 2.71 [95% CI 2.04-3.60], p<0.0001 and CFS4-5 vs CFS1-3 OR 1.54 [1.16-2.06], p=0.0030; age >= 65 years: CFS6-9 vs CFS1-3 OR 2.90 [2.12-3.97], p<0.0001 and CFS4-5 vs CFS1-3 OR 1.64 [1.20-2.25], p=0.0020). In patients younger than 65 years, an increased hospital mortality risk was only observed in frail patients (CFS6-9 vs CFS1-3 OR 2.22 [1.08-4.57], p=0.030; CFS4-5 vs CFS1-3 OR 1.08 [0.48-2.39], p=0.86). Frail patients had a higher incidence of admission to intensive care than fit patients (CFS6-9 vs CFS1-3 OR 1.54 [1.21-1.97], p=0.0010), whereas mildly frail patients had a lower incidence than fit patients (CFS4-5 vs CFS1-3 OR 0.71 [0.55-0.92], p=0.0090). Among patients younger than 65 years, frail patients had an increased incidence of admission to intensive care (CFS6-9 vs CFS1-3 OR 2.96 [1.98-4.43], p<0.0001), whereas mildly frail patients had no significant difference in incidence compared with fit patients (CFS4-5 vs CFS1-3 OR 0.93 [0.63-1.38], p=0.72). Among patients aged 65 years and older, frail patients had no significant difference in the incidence of admission to intensive care compared with fit patients (CFS6-9 vs CFS1-3 OR 1.27 [0.92-1.75], p=0.14), whereas mildly frail patients had a lower incidence than fit patients (CFS4-5 vs CFS1-3 OR 0.66 [0.47-0.93], p=0.018).Interpretation The results of this study suggest that CFS score is a suitable risk marker for hospital mortality in adult patients with COVID-19. However, treatment decisions based on the CFS in patients younger than 65 years should be made with caution. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
