Purpose:Simple bone cysts are among the most prevalent benign cystic tumor-like lesions in children. Proximal femoral simple bone cysts may require specific treatment because of increased fracture... Show morePurpose:Simple bone cysts are among the most prevalent benign cystic tumor-like lesions in children. Proximal femoral simple bone cysts may require specific treatment because of increased fracture risk. With limited literature available on this specific localization, consensus regarding optimal treatment is lacking. We present a large international multicenter retrospective cohort study on proximal femoral simple bone cysts.Methods:All consecutive pediatric patients with proximal femoral simple bone cyst from 10 tertiary referral centers for musculoskeletal oncology were included (2000–2021). Demographics, primary treatment, complications, and re-operations were evaluated. Primary outcomes were time until full weight-bearing and failure-free survival.Results:Overall, 74 simple bone cyst patients were included (median age 9 years (range = 2–16), 56 (76%) male). Median follow-up was 2.9 years (range = 0.5–21). Index procedure was watchful waiting (n = 6), percutaneous procedure (n = 12), open procedure (n = 50), or osteosynthesis alone (n = 6). Median time until full weight-bearing was 8 weeks (95% confidence interval = 0.1–15.9) for watchful waiting, 9.5 (95% confidence interval = 3.7–15.3) for percutaneous procedure, 11 (95% confidence interval = −0.7 to 13.7) for open procedure, and 6.5 (95% confidence interval = 5.9–16.1) for osteosynthesis alone (p = 0.58). Failure rates were 33%, 58%, 29%, and 0%, respectively (p = 0.069). Overall failure-free survival at 1, 2, and 5 years was 77.8% (95% confidence interval = 68.2–87.4), 69.5% (95% confidence interval = 58.5–80.5), and 62.0% (95% confidence interval = 47.9–76.1), respectively.Conclusion:A preferred treatment for proximal femoral simple bone cysts remains unclear, with comparable failure rates and times until full weight-bearing. Watchful waiting may be successful in certain cases. If not feasible, osteosynthesis alone can be considered. Treatment goals should be cyst control, minimizing complications and swift return to normal activities. Therefore, an individualized balance should be made between undertreatment, with potentially higher complication risks versus overtreatment, resulting in possible larger interventions and accompanying complications.Level of evidence:Level IV, retrospective multicentre study Show less
Gomon, D.; Putter, H.; Fiocco, M.; Signorelli, M. 2024
BackgroundDexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and... Show moreBackgroundDexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors.MethodsPatients with ALL aged 3-18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or >= three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2.ResultsWe included 105 patients, 61% were boys. Median age was 5.3 years (range: 3-18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28-0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22-0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96-0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2-3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2.ConclusionPhysical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course.Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy. After a 5-day dexamethasone course. Physical frailty increased with 13.5% in pediatric ALL patients. A poorer physical state at start of a dexamethasone course (lower muscle mass, muscle strength, or slower movement ability) was prognostic for developing frailty after a dexamethasone course.image Show less
Pluimakers, V.G.; Atteveld, J.E. van; Winter, D.T.C. de; Bolier, M.; Fiocco, M.; Nievelstein, R.J.A.J.; ... ; Neggers, S.J.C.M.M. 2023
Background: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual... Show moreBackground: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual-energy X-ray absorptiometry (DXA). We aimed to assess prevalence, identify determinants and biomarkers, and assess which method captures overweight best, in a nationwide cohort.Methods: The prevalence of overweight and obesity, primarily defined by body mass index (BMI), was assessed in the DCCSS-LATER cohort of adult survivors treated from 1963-2002, with the LifeLines cohort as reference. The associations between risk factors and overweight metrics were investigated using logistic regression. Additional overweight metrics included DXA fat%, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and high-molecular-weight (HMW) adiponectin.Results: A total of 2338 (mean age 35.5 years, follow-up 28.3 years) survivors participated. The overweight prevalence was 46.3% in men and 44.3% in women (obesity 11.2% and 15.9%, morbid obesity 2.4% and 5.4%), with highest rates among brain tumor survivors. Compared to controls, there was no overall increased overweight rate, but this was higher in women > 50 years, morbid obesity in men > 50 years. Overweight at cancer diagnosis (adjusted odds ratio [aOR] = 3.83, 95% CI 2.19-6.69), cranial radiotherapy (aOR = 3.21, 95% CI 1.99-5.18), and growth hormone deficiency (separate model, aOR = 1.61, 95% CI 1.00-2.59) were associated with overweight. Using BMI, WC, WHR, and WHtR, overweight prevalence was similar. Low HMW adiponectin, present in only 4.5% of survivors, was an insensitive overweight marker. Dual-energy X-ray absorptiometry-based classification identified overweight in an additional 30%, particularly after abdominal radiotherapy, total body irradiation, anthracyclines, and platinum.Conclusions: Overweight occurs in almost half of long-term survivors. There was no overall increased incidence of overweight compared to controls. We identified factors associated with overweight, as well as subgroups of survivors in whom DXA can more reliably assess overweight. Show less
Hulst, A.M. van; Verwaaijen, E.J.; Berg, S.A.A. van den; Litsenburg, R.R.L. van; Grootenhuis, M.A.; Fiocco, M.; ... ; Akker, E.L.T. van den 2023
Background & aims: Children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone during treatment, which induce acute side effects. The aims of the current study were to... Show moreBackground & aims: Children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone during treatment, which induce acute side effects. The aims of the current study were to determine the influence of a five-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep and fatigue and to explore associations between these changes.Methods: Pediatric ALL patients were included during maintenance treatment. Data was collected before (T1) and after (T2) a five-day dexamethasone course (6 mg/m(2)/day). BMI, fat mass (bioelectrical impedance analysis) and leptin were assessed on both timepoints, as well as parent-reported questionnaires regarding hunger, fatigue and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin.Results: We included 105 children with median age 5.4 years (range 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue and sleep deteriorated after five days of dexamethasone (p < 0.001), in contrast to BMI (p = 0.12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio (OR) 1.51, 95%-confidence interval (95%-CI) 1.28-1.77), higher fat mass (OR 1.19, 95%-CI 1.07-1.33) and earlier maintenance week (OR 0.96, 95%-CI 0.92-0.99).Conclusions: Five days of high dose dexamethasone treatment lead to direct and significant changes in leptin, hunger scores and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role. Show less
Gomon, D.; Sijmons, J.; Putter, H.; Dekker, J.W.; Tollenaar, R.; Wouters, M.; ... ; Signorelli, M. 2023
During the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care... Show moreDuring the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care provided at each hospital is essential to improve patient outcomes. It is unclear which methods should be used to generate most informative output for the identification of potential quality issues. Our aim is to compare the commonly employed funnel plot with existing cumulative sum (CUSUM) methodology for the evaluation of postoperative survival and hospital stay outcomes of patients who underwent colorectal surgery in the Netherlands. Data from the Dutch ColoRectal Audit on 25367 patients in the Netherlands who underwent surgical resection for colorectal cancer in 71 hospitals between 2019 and 2021 is used to compare four methods for the detection of deviations in the quality of care. Two methods based on binary outcomes (funnel plot, binary CUSUM) and two CUSUM charts based on survival outcomes (BK-CUSUM and CGR-CUSUM) are considered. A novel approach for determining hospital specific control limits for CUSUM charts is proposed. The ability to detect deviations as well as the time until detection are compared for the four methods. Charts were constructed for the inspection of both postoperative survival and hospital stay. Methods using survival outcomes always yielded faster detection times compared to approaches employing binary outcomes. Detections between methods mostly coincided for postoperative survival. For hospital stay detections varied strongly, with methods based on survival outcomes signalling over half the hospitals. Further pros and cons as well as pitfalls of all methods under consideration are discussed. Methodology for the continuous inspection of the quality of care should be tailored to the specific outcome. Properly understanding how the mechanism of a control chart functions is crucial for the correct interpretation of results. This is particularly true for CUSUM charts, which require the choice of a parameter that greatly influences the results. When applying CUSUM charts, consideration of these issues is strongly recommended. Show less
Gomon, D.; Sijmons, J.; Putter, H.; Dekker, J.W.; Tollenaar, R.; Wouters, M.; ... ; Signorelli, M. 2023
During the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of... Show moreDuring the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care provided at each hospital is essential to improve patient outcomes. It is unclear which methods should be used to generate most informative output for the identification of potential quality issues. Our aim is to compare the commonly employed funnel plot with existing cumulative sum (CUSUM) methodology for the evaluation of postoperative survival and hospital stay outcomes of patients who underwent colorectal surgery in the Netherlands. Data from the Dutch ColoRectal Audit on 25367 patients in the Netherlands who underwent surgical resection for colorectal cancer in 71 hospitals between 2019 and 2021 is used to compare four methods for the detection of deviations in the quality of care. Two methods based on binary outcomes (funnel plot, binary CUSUM) and two CUSUM charts based on survival outcomes (BK-CUSUM and CGR-CUSUM) are considered. A novel approach for determining hospital specific control limits for CUSUM charts is proposed. The ability to detect deviations as well as the time until detection are compared for the four methods. Charts were constructed for the inspection of both postoperative survival and hospital stay. Methods using survival outcomes always yielded faster detection times compared to approaches employing binary outcomes. Detections between methods mostly coincided for postoperative survival. For hospital stay detections varied strongly, with methods based on survival outcomes signalling over half the hospitals. Further pros and cons as well as pitfalls of all methods under consideration are discussed. Methodology for the continuous inspection of the quality of care should be tailored to the specific outcome. Properly understanding how the mechanism of a control chart functions is crucial for the correct interpretation of results. This is particularly true for CUSUM charts, which require the choice of a parameter that greatly influences the results. When applying CUSUM charts, consideration of these issues is strongly recommended. Show less
Brink, P.; Kalisvaart, G.M.; Schrage, Y.M.; Mohammadi, M.; Ijzerman, N.S.; Bleckman, R.F.; ... ; Hage, J.A. van der 2023
BackgroundThe added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of... Show moreBackgroundThe added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database.MethodsA survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment.ResultsThe survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336–0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195–12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082–0.880) were associated with worse and better survival after local treatment, respectively.ConclusionLocal treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study. Show less
Pieters, R.; Groot-Kruseman, H. de; Fiocco, M.; Verwer, F.; Overveld, M. van; Sonneveld, E.; ... ; Boer, M. den 2023
Purpose The ALL10 protocol improved outcomes for children with ALL by stratifying and adapting therapy into three minimal residual disease-defined risk groups: standard risk, medium risk (MR), and... Show morePurpose The ALL10 protocol improved outcomes for children with ALL by stratifying and adapting therapy into three minimal residual disease-defined risk groups: standard risk, medium risk (MR), and high risk. IKZF1-deleted (IKZF1del) ALL in the largest MR group still showed poor outcome, in line with protocols worldwide, accounting for a high number of overall relapses. ALL10 showed high toxicity in Down syndrome (DS) and excellent outcome in ETV6::RUNX1 ALL. Poor prednisone responders (PPRs) were treated as high risk in ALL10. In ALL11, we prolonged therapy for IKZF1del from 2 to 3 years. We reduced therapy for DS by omitting anthracyclines completely, for ETV6::RUNX1 in intensification, and for PPR by treatment as MR.Methods Eight hundred nineteen patients with ALL (age, 1-18 years) were enrolled on ALL11 and stratified as in ALL10. Results were compared with those in ALL10.Results The five-year overall survival (OS), event-free survival (EFS), cumulative risk of relapse (CIR), and death in complete remission on ALL11 were 94.2% (SE, 0.9%), 89.0% (1.2), 8.2% (1.1), and 2.3% (0.6), respectively. Prolonged maintenance for IKZF1del MR improved 5-year CIR by 2.2-fold (10.8% v 23.4%; P = .035) and EFS (87.1% v 72.3%; P = .019). Landmark analysis at 2 years from diagnosis showed a 2.9-fold reduction of CIR (25.6%-8.8%; P = .008) and EFS improvement (74.4%-91.2%; P = .007). Reduced therapy did not abrogate 5-year outcome for ETV6::RUNX1 (EFS, 98.3%; OS, 99.4%), DS (EFS, 87.0%; OS, 87.0%), and PPR (EFS, 81.1%; OS, 94.9%).Conclusion Children with IKZF1del ALL seem to benefit from prolonged maintenance therapy. Chemotherapy was successfully reduced for patients with ETV6::RUNX1, DS, and PPR ALL. It has to be noted that these results were obtained in a nonrandomized study using a historical control group. Show less
Lebbink, C.A.; Bresters, D.; Tersteeg, J.P.B.; Bos, C. van den; Dierselhuis, M.P.; Lentjes, E.G.W.M.; ... ; Santen, H.M. van 2023
Background Thyroid dysfunction (hypo- and hyperthyroidism) has been reported as a late effect after hematopoietic stem cell transplantation (HSCT) in children. Short-term effects of HSCT on thyroid... Show moreBackground Thyroid dysfunction (hypo- and hyperthyroidism) has been reported as a late effect after hematopoietic stem cell transplantation (HSCT) in children. Short-term effects of HSCT on thyroid function parameters are, however, unclear. Methods We prospectively evaluated thyroid function parameters before and 3 months after HSCT in all children (<21 years) who underwent HSCT during a 2-year period in the Princess Maxima Center, the Netherlands. Results Among 72 children, none had thyroidal hypothyroidism or hyperthyroidism 3 months after HSCT. Changes in thyroid function parameters (either aberrant thyroid-stimulating hormone [TSH] or free thyroxine [FT4] concentrations) were found in 16% before and in 10% 3 months after HSCT. Reverse triiodothyronine (rT3) was found elevated in 9.3% before and in 37% 3 months after HSCT, which could be related to poor physical condition. An individual decline in FT4 concentration of & GE;20% was found in 10.5% (6/57) 3 months after HSCT. Conclusion In conclusion, thyroidal hypo- and hyperthyroidism are very rare 3 months after HSCT. These results indicate that surveillance for hypo- and hyperthyroidism may start later in time. The changes in thyroid function parameters found 3 months after HSCT might reflect euthyroid sick syndrome. Show less
Hulst, A.M. van; Akker, E.L.T. van den; Verwaaijen, E.J.; Fiocco, M.; Rensen, N.; Litsenburg, R.R.L. van; ... ; Heuvel-eibrink, M.M. van den 2023
Background: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who... Show moreBackground: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding.Methods: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect.Results: The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect-2.05 (95% confidence interval (CI)-6.00-1.90). Also, no benefit from hydrocortisone compared to pla-cebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL.Conclusions: Hydrocortisone, when compared to placebo, had no additional effect in redu-cing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hy-drocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Trial registration: NetherlandsTrial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/).(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). Show less
Arntzen, V.H.; Fiocco, M.; Leitzinger, N.; Geskus, R.B. 2023
Quarantine length for individuals who have been at risk for infection with SARS-CoV-2 has been based on estimates of the incubation time distribution. The time of infection is often not known... Show moreQuarantine length for individuals who have been at risk for infection with SARS-CoV-2 has been based on estimates of the incubation time distribution. The time of infection is often not known exactly, yielding data with an interval censored time origin. We give a detailed account of the data structure, likelihood formulation and assumptions usually made in the literature: (i) the risk of infection is assumed constant on the exposure window and (ii) the incubation time follows a specific parametric distribution. The impact of these assumptions remains unclear, especially for the right tail of the distribution which informs quarantine policy. We quantified bias in percentiles by means of simulation studies that mimic reality as close as possible. If assumption (i) is not correct, then median and upper percentiles are affected similarly, whereas misspecification of the parametric approach (ii) mainly affects upper percentiles. The latter may yield considerable bias. We suggest a semiparametric method that provides more robust estimates without the need of a parametric choice. Additionally, we used a simulation study to evaluate a method that has been suggested if all infection times are left censored. It assumes that the width of the interval from infection to latest possible exposure follows a uniform distribution. This assumption gave biased results in the exponential phase of an outbreak. Our application to open source data suggests that focus should be on the level of information in the observations, as expressed by the width of exposure windows, rather than the number of observations. Show less
Meer, P.B. van der; Dirven, L.; Fiocco, M.; Vos, M.J.; Kouwenhoven, M.C.M.; Bent, M.J. van den; ... ; Koekkoek, J.A.F. 2023
Background and ObjectivesApproximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate... Show moreBackground and ObjectivesApproximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate whether levetiracetam combined with valproic acid and clobazam (LEV + VPA + CLB), a frequently prescribed triple therapy, has favorable effectiveness compared with other triple therapy combinations in patients with glioma.MethodsThis was a multicenter retrospective observational cohort study. The primary outcome was the cumulative incidence of time to treatment failure for any reason, from the start of ASM triple therapy treatment. The secondary outcomes included cumulative incidences of the following: (1) time to treatment failure due to uncontrolled seizures; (2) time to treatment failure due to adverse effects; and (3) time to recurrent seizures. Patients were followed up for a maximum duration of 36 months.ResultsOf 1,435 patients in the original cohort, 90 patients received ASM triple therapy after second-line ASM treatment failure due to uncontrolled seizures. LEV + VPA + CLB was prescribed to 48% (43/90) and other ASM triple therapy to 52% (47/90) of patients. The cumulative incidence of treatment failure for any reason of LEV + VPA + CLB did not statistically significantly differ from that of other ASM triple therapy combinations (12 months: 47% [95% CI 31%–62%] vs 42% [95% CI 27%–56%], p = 0.892). No statistically significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95% CI 4%–25%] vs 18% [95% CI 8%–30%], p = 0.445), adverse effects (12 months: 22% [95% CI 11%–36%] vs 15% [95% CI 7%–27%], p = 0.446), or recurrent seizures (1 month: 65% [95% CI 48%–78%] vs 63% [95% CI 47%–75%], p = 0.911) were found. Show less
Atteveld, J.E.; Winter, D.T.C. de; Pluimakers, V.G.; Fiocco, M.; Nievelstein, R.A.J.; Hobbelink, M.G.G.; ... ; Dutch LATER study grp 2023
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
Lemij, A.A.; Liefers, G.J.; Derks, M.G.M.; Bastiaannet, E.; Fiocco, M.; Lans, T.E.; ... ; Glas, N.A. de 2023
Background A decline in physical activity and the ability to perform activities of daily living (ADL) and instrumental activities of daily living (IADL) could interfere with independent living and... Show moreBackground A decline in physical activity and the ability to perform activities of daily living (ADL) and instrumental activities of daily living (IADL) could interfere with independent living and quality of life in older patients, but may be prevented with tailored interventions. The aim of the current study was to assess changes in physical activity and ADL/IADL in the first 5 years after breast cancer diagnosis in a real-world cohort of older patients and to identify factors associated with physical decline. Methods Patients aged >= 70 years with in situ or stages I-III breast cancer were included in the prospective Climb Every Mountain cohort study. Linear mixed models were used to assess physical activity (according to Metabolic Equivalent of Task (MET) hours per week) and ADL/IADL (according to the Groningen Activity Restriction Scale (GARS)) over time. Secondly, the association with geriatric characteristics, treatment, quality of life, depression, apathy, and loneliness was analyzed. Results A total of 239 patients were included. Physical activity and ADL/IADL changed in the first 5 years after diagnosis (mean change from baseline -11.6 and +4.2, respectively). Geriatric characteristics at baseline were strongly associated with longitudinal change in physical activity and ADL/IADL, whereas breast cancer treatment was not. A better quality of life was associated with better physical activity and preservation of ADL/IADL, while depression and loneliness were negatively associated with these outcomes. Discussion Geriatric characteristics, loneliness, and depressive symptoms were associated with physical decline in older patients with breast cancer, while breast cancer treatment was not.A decline in physical activity and the ability to perform activities of daily living may interfere with quality of life in older patients. This article assessed changes in physical activity and activities of daily living in the first 5 years after breast cancer diagnosis in a real-world cohort of older patients and identified factors associated with physical decline. Show less
Introduction: Studies investigating the long-term effects of breast cancer treatment on cognition in older women with breast cancer are lacking, even though preserving cognition is highly valued by... Show moreIntroduction: Studies investigating the long-term effects of breast cancer treatment on cognition in older women with breast cancer are lacking, even though preserving cognition is highly valued by the older population. Specifically, concerns have been raised regarding the detrimental effects of endocrine therapy (ET) on cognition. Therefore, we investigated cogni-tive functioning over time and predictors for cognitive decline in older women treated for early breast cancer.Methods: We prospectively enrolled Dutch women aged >70 years with stage I-III breast can-cer in the observational CLIMB study. The Mini-Mental State Examination (MMSE) was performed before ET initiation and after 9, 15 and 27 months. Longitudinal MMSE scores were analysed and stratified for ET. Linear mixed models were used to identify possible pre-dictors of cognitive decline.Results: Among the 273 participants, the mean age was 76 years (standard deviation 5), and 48% received ET. The mean baseline MMSE score was 28.2 (standard deviation 1.9). Cogni-tion did not decline to clinically meaningful differences, irrespective of ET. MMSE scores of women with pre-treatment cognitive impairments slightly improved over time (significant interaction terms) in the entire cohort and in women receiving ET. High age, low educational level and impaired mobility were independently associated with declining MMSE scores over time, although the declines were not clinically meaningful.Conclusion: Cognition of older women with early breast cancer did not decline in the first two years after treatment initiation, irrespective of ET. Our findings suggest that the fear of declining cognition does not justify the de-escalation of breast cancer treatment in older women. 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Lebbink, C.A.; Bos, C. van den; Dierselhuis, M.P.; Fiocco, M.; Stuart, A.A.V.; Lentjes, E.G.W.M.; ... ; Santen, H.M. van 2023
Simple Summary Thyroid dysfunction during childhood may affect daily energy, growth, body mass index and bone development. Thyroid dysfunction may occur in children with cancer due to chemotherapy... Show moreSimple Summary Thyroid dysfunction during childhood may affect daily energy, growth, body mass index and bone development. Thyroid dysfunction may occur in children with cancer due to chemotherapy or other drugs, radiotherapy, the tumor itself or severe illness. The aim of this prospective study was to determine the percentage, severity and risk factors of changing thyroid hormone concentrations in the first three months of childhood cancer treatment. Subclinical hypothyroidism (normal thyroid hormones, with elevated thyroid stimulating hormone (TSH) according to age) was present in 8.2% of children at diagnosis and 2.9% of children three months after starting treatment. Subclinical hyperthyroidism (normal thyroid hormones, with lowered TSH values according to age) was present in 3.6% of children at diagnosis and 0.7% of children after three months. In 28% of children, the concentration of free thyroid hormone (FT4) decreased by >= 20%. We conclude that children with cancer are at low risk of developing hypo- or hyperthyroidism in the first three months after starting treatment but may develop a decline in FT4. Background: Thyroid hormone anomalies during childhood might affect neurological development, school performance and quality of life, as well as daily energy, growth, body mass index and bone development. Thyroid dysfunction (hypo- or hyperthyroidism) may occur during childhood cancer treatment, although its prevalence is unknown. The thyroid profile may also change as a form of adaptation during illness, which is called euthyroid sick syndrome (ESS). In children with central hypothyroidism, a decline in FT4 of >20% has been shown to be clinically relevant. We aimed to quantify the percentage, severity and risk factors of a changing thyroid profile in the first three months of childhood cancer treatment. Methods: In 284 children with newly diagnosed cancer, a prospective evaluation of the thyroid profile was performed at diagnosis and three months after starting treatment. Results: Subclinical hypothyroidism was found in 8.2% and 2.9% of children and subclinical hyperthyroidism in 3.6% and in 0.7% of children at diagnosis and after three months, respectively. ESS was present in 1.5% of children after three months. In 28% of children, FT4 concentration decreased by >= 20%. Conclusions: Children with cancer are at low risk of developing hypo- or hyperthyroidism in the first three months after starting treatment but may develop a significant decline in FT4 concentrations. Future studies are needed to investigate the clinical consequences thereof. Show less
Kantidakis, G.; Putter, H.; Litière, S.; Fiocco, M. 2023
BackgroundIn health research, several chronic diseases are susceptible to competing risks (CRs). Initially, statistical models (SM) were developed to estimate the cumulative incidence of an event... Show moreBackgroundIn health research, several chronic diseases are susceptible to competing risks (CRs). Initially, statistical models (SM) were developed to estimate the cumulative incidence of an event in the presence of CRs. As recently there is a growing interest in applying machine learning (ML) for clinical prediction, these techniques have also been extended to model CRs but literature is limited. Here, our aim is to investigate the potential role of ML versus SM for CRs within non-complex data (small/medium sample size, low dimensional setting).MethodsA dataset with 3826 retrospectively collected patients with extremity soft-tissue sarcoma (eSTS) and nine predictors is used to evaluate model-predictive performance in terms of discrimination and calibration. Two SM (cause-specific Cox, Fine-Gray) and three ML techniques are compared for CRs in a simple clinical setting. ML models include an original partial logistic artificial neural network for CRs (PLANNCR original), a PLANNCR with novel specifications in terms of architecture (PLANNCR extended), and a random survival forest for CRs (RSFCR). The clinical endpoint is the time in years between surgery and disease progression (event of interest) or death (competing event). Time points of interest are 2, 5, and 10 years.ResultsBased on the original eSTS data, 100 bootstrapped training datasets are drawn. Performance of the final models is assessed on validation data (left out samples) by employing as measures the Brier score and the Area Under the Curve (AUC) with CRs. Miscalibration (absolute accuracy error) is also estimated. Results show that the ML models are able to reach a comparable performance versus the SM at 2, 5, and 10 years regarding both Brier score and AUC (95% confidence intervals overlapped). However, the SM are frequently better calibrated.ConclusionsOverall, ML techniques are less practical as they require substantial implementation time (data preprocessing, hyperparameter tuning, computational intensity), whereas regression methods can perform well without the additional workload of model training. As such, for non-complex real life survival data, these techniques should only be applied complementary to SM as exploratory tools of model's performance. More attention to model calibration is urgently needed. Show less
Praag, V.M. van; Fiocco, M.; Bleckman, R.F.; Houdt, W.J. van; Haas, R.L.M.; Verhoef, C.; ... ; Sande, M.A.J. van de 2023
Introduction: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb... Show moreIntroduction: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfu-sion (ILP).In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies.Methods: All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years. Results: Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group.Conclusion: We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
