Better tools for better estimates: improving approaches to handling missing data in Swiss cancer registries.

OBJECTIVE: Various approaches have been used in the literature to handle missing vital status data in cancer registries. We aimed to compare these approaches to determine which led to the least biased estimates in typical analytic tasks of cancer registries. METHODS: A simulation study was performed using data from the Swiss National Agency for Cancer Registration for six tumor types. First, 5%, 10% and 15% missingness in the vital status were introduced artificially in the complete data. Second, missing vital status data were handled by applying no, single or multiple imputations. Five-year overall survival estimates, relative survival or standardized incidence ratio were computed. Estimates were compared with the true value. RESULTS: Standardized incidence ratio estimates for colorectal cancer obtained with multiple imputation yielded least biased results (-0.06 to -0.04), but the widest confidence intervals. Single imputation was more biased (-0.32) than using no imputation at all (-0.21). A similar pattern was observed for overall survival and relative survival. CONCLUSION: This simulation study indicated that often used single imputation (sometimes referred to as simulating follow-up times) techniques to fill in missing vital status data are likely too biased to be useful in practice. Multiple imputation approaches yielded standardized incidence ratio, overall and relative survival estimates with the least bias, indicating reasonable performance that is likely to generalize to other settings.

Experts vs. machine - comparison of machine learning to expert-informed prediction of outcome after major liver surgery.

BACKGROUND: Machine learning (ML) has been successfully implemented for classification tasks (e.g., cancer diagnosis). ML performance for more challenging predictions is largely unexplored. This study's objective was to compare machine learning vs. expert-informed predictions for surgical outcome in patients undergoing major liver surgery. METHODS: Single tertiary center data on preoperative parameters and postoperative complications for elective hepatic surgery patients were included (2008-2021). Expert-informed prediction models were established on 14 parameters identified by two expert liver surgeons to impact on postoperative outcome. ML models used all available preoperative patient variables (n = 62). Model performance was compared for predicting 3-month postoperative overall morbidity. Temporal validation and additional analysis in major liver resection patients were conducted. RESULTS: 889 patients included. Expert-informed models showed low average bias (2-5 CCI points) with high over/underprediction. ML models performed similarly: average prediction 5-10 points higher than observed CCI values with high variability (95% CI -30 to 50). No performance improvement for major liver surgery patients. CONCLUSION: No clinical relevance in the application of ML for predicting postoperative overall morbidity was found. Despite being a novel hype, ML has the potential for application in clinical practice. However, at this stage it does not replace established approaches of prediction modelling.

Surgical outcome improvement by shared decision-making: value of a preoperative multidisciplinary target clinic for the elderly in colorectal surgery.

PURPOSE: Frailty and comorbidities increase the risk of postoperative complications and raise treatment costs. Perioperative optimisation is shown to improve surgical outcomes for the elderly. The aim of this study was to assess the impact of introducing a multidisciplinary preoperative clinic for older patients (Colchester Older Persons' Evaluation for Surgery (COPES) clinic) undergoing major colorectal surgery. METHODS: This 5-year single centre study included patients >65 years with ≥3 comorbidities undergoing major colorectal surgery. From October 2018, patients with these characteristics were evaluated and optimised in the COPES clinic by a geriatrician and an anaesthetist. Outcomes were compared to high-risk patients operated on prior to COPES (pre-COPES group). The primary outcomes were postoperative morbidity at discharge and 6 months measured by the Comprehensive Complication Index. Patients were matched on age and number of comorbidities. RESULTS: A total of 54 patients were enrolled in the pre-COPES and 18 in the COPES group. After matching, the results were comparable for both groups. The length of stay was shorter in the COPES group and the recurrence rate was higher; however, it did not reach statistical significance in both findings. CONCLUSION: This clinic intends to improve treatment quality, placing emphasis on shared decision-making. More focus should be put on patient-reported outcomes and experiences. Especially for elderly patients, quality of life and maintaining independence are often their priority. To determine the true value of a preoperative multidisciplinary clinic targeting elderly comorbid patients, a prospective study with larger cohort is needed, focusing not only on objective outcomes but also on patient-reported outcomes.

There is no evidence that carbon dioxide-enriched oxygen before apnea affects the time to arterial desaturation, but it might improve cerebral oxygenation in anesthetized obese patients: a single-blinded randomized crossover trial.

PURPOSE: Carbon dioxide (CO2) increases cerebral perfusion. The effect of CO2 on apnea tolerance, such as after anesthesia induction, is unknown. This study aimed to assess if cerebral apnea tolerance can be improved in obese patients under general anesthesia when comparing O2/Air (95%O2) to O2/CO2 (95%O2/5%CO2). METHODS: In this single-center, single-blinded, randomized crossover trial, 30 patients 18-65 years, with body mass index > 35 kg/m2, requiring general anesthesia for bariatric surgery, underwent two apneas that were preceded by ventilation with either O2/Air or O2/CO2 in random order. After anesthesia induction, intubation, and ventilation with O2/Air or O2/CO2 for 10 min, apnea was performed until the cerebral tissue oxygenation index (TOI) dropped by a relative 20% from baseline (primary endpoint) or oxygen saturation (SpO2) reached 80% (safety abortion criterion). The intervention was then repeated with the second substance. RESULTS: The safety criterion was reached in all patients before cerebral TOI decreased by 20%. The time until SpO2 dropped to 80% was similar in the two groups (+ 6 s with O2/CO2, 95%CI -7 to 19 s, p = 0.37). Cerebral TOI and PaO2 were higher after O2/CO2 (+ 1.5%; 95%CI: from 0.3 to 2.6; p = 0.02 and + 0.6 kPa; 95%CI: 0.1 to 1.1; p = 0.02). CONCLUSION: O2/CO2 improves cerebral TOI and PaO2 in anesthetized bariatric patients. Better apnea tolerance could not be confirmed.

Respiratory morbidity in preschool and school-age children born very preterm and its association with parents' health-related quality of life and family functioning.

The purpose of this study is to describe the prevalence and severity of respiratory symptoms in children born very preterm and to assess their association with parents' health-related quality of life (HRQoL) and family functioning. We conducted a cross-sectional study and recruited children born less than 32 weeks' gestation between January 2006 and December 2019, in the greater Zurich area, Switzerland. Between May and December 2021, parents were invited to complete an online survey for their preterm child and for a control term born (≥ 37 weeks' gestation) sibling aged 1 to 18 years. We used a validated questionnaire to assess respiratory symptoms and the Pediatrics Quality of Life Family Impact Module (PedsQL FIM) to assess parents' HRQoL and family functioning. The survey was completed for 616 very preterm children (99 with bronchopulmonary dysplasia (BPD)) and 180 controls. Girls made up 45% (46% in controls) of the sample, and 63% (60% in controls) of participants were aged 6 to 18 years (school-age). Very preterm children reported a higher risk of respiratory symptoms than controls, especially preschoolers and those with moderate-to-severe BPD. Parents of children with "mild" and "moderate-severe" respiratory symptoms had on average -3.9 (95%CI: -6.6 to -1.1) and -8.2 (-11.2 to -5.2) lower PedsQL FIM total score, respectively, than parents of children with no symptoms. The same pattern was observed after stratifying by age categories.  Conclusions: Our study suggests that respiratory morbidity in very preterm children has a negative impact on parents' HRQoL and family functioning, even beyond the first years of life. What is Known: • The burden of respiratory morbidity associated with very premature birth is high and last far beyond the neonatal period. • Respiratory morbidity contributes to lower health-related quality of life (HRQoL) in parents of very preterm children in early infancy. What is New: • Respiratory morbidity in very preterm children has a negative impact on parents' HRQoL and family functioning beyond the first years of life. • Parents of very preterm children with moderate and severe respiratory symptoms are the ones who report lower scores, both for preschool and school-age children.

Cystic fibrosis related diabetes is not associated with maximal aerobic exercise capacity in cystic fibrosis: a cross-sectional analysis of an international multicenter trial.

BACKGROUND: Previous studies have reported differences in aerobic exercise capacity, expressed as peak oxygen uptake (VO2peak), between people with and without cystic fibrosis (CF) related diabetes (CFRD). However, none of the studies controlled for the potential influence of physical activity on VO2peak. We investigated associations between CFRD and VO2peak following rigorous control for confounders including objectively measured physical activity. METHODS: Baseline data from the international multicenter trial ACTIVATE-CF with participants ≥12 years performing up to 4 h per week of vigorous physical activity were used for this project. Multivariable models were computed to study associations between CFRD and VO2peak (mL.min-1) adjusting for a set of pre-defined covariates: age, sex, weight, forced expiratory volume in 1 s (FEV1), breathing reserve index, Pseudomonas aeruginosa infection, and physical activity (aerobic step counts from pedometry). Variables were selected based on their potential confounding effect on the association between VO2peak and CFRD. RESULTS: Among 117 randomized individuals, 103 (52% female) had a maximal exercise test and were included in the analysis. Participants with (n = 19) and without (n = 84) CFRD did not differ in FEV1, physical activity, nutritional status, and other clinical characteristics. There were also no differences in VO2peak (mL.min-1 or mL.kg-1.min-1 or% predicted). In the final multivariable model, all pre-defined covariates were significant predictors of VO2peak (mL.min-1), however CFRD [coefficient 82.1, 95% CI -69.5 to 233.8, p = 0.28] was not. CONCLUSIONS: This study suggests no meaningful differences in VO2peak between people with and without CFRD given comparable levels of physical activity.

Survival modelling and cost-effectiveness analysis of treatments for newly diagnosed metastatic hormone-sensitive prostate cancer.

BACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC) treatment, survival benefits have been shown by adding docetaxel or recent androgen receptor axis-targeted therapies (ARATs) abiraterone, apalutamide, or enzalutamide to androgen deprivation therapy (ADT). However, the optimal treatment strategy in terms of costs and effects is unclear, not least due to high ARAT costs. METHODS: To assess treatment cost-effectiveness, we developed a Markov cohort model with health states of progression-free disease, progressive disease and death for men with newly diagnosed mHSPC, with a 30-year time horizon. Survival data, adverse events and utilities were informed by randomized controlled trial results, our meta-analysis of re-created individual patient survival data, and publicly available sources of unit costs. We applied a Swiss healthcare payer perspective and discounted costs and effects by 3%. RESULTS: We found a significant overall survival benefit for ADT+abiraterone versus ADT+docetaxel. The corresponding incremental cost-effectiveness ratio (ICER) was predicted to be EUR 39,814 per quality-adjusted life-year (QALY) gained. ADT+apalutamide and ADT+enzalutamide incurred higher costs and lower QALYs compared to ADT+abiraterone. For all ARATs, drug costs constituted the most substantial cost component. Results were stable except for a large univariable reduction in the pre-progression utility under ADT+abiraterone and very large variations in drug prices. CONCLUSIONS: Our model projected ADT+abiraterone to be cost-effective compared to ADT+docetaxel at a willingness-to-pay threshold of EUR 70,400/QALY (CHF 100,000 applying purchasing power parities). Given lower estimated QALYs for ADT+apalutamide and ADT+enzalutamide compared to ADT+abiraterone, the former only became cost-effective (the preferred) treatment option(s) at substantial 75-80% (80-90%) price reductions.

Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment.

CONTEXT: Multiple treatments for metastatic, hormone-sensitive prostate cancer (mHSPC) are available, but their effects on health-related quality of life (HRQoL) and benefit-harm balance remain unclear. OBJECTIVE: To assess clinical effectiveness regarding survival and HRQoL, safety, and benefit-harm balance of mHSPC treatments. EVIDENCE ACQUISITION: We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov until March 1, 2022. Randomized controlled trials (RCTs) comparing docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, and radiotherapy combined with androgen deprivation therapy (ADT) mutually or with ADT alone were eligible. Three reviewers independently performed screening, data extraction, and risk of bias assessment in duplicate. EVIDENCE SYNTHESIS: Across ten RCTs, we found relevant survival benefits for ADT + docetaxel (high certainty according to the Grading of Recommendations, Assessment, Development and Evaluation [GRADE]), ADT + abiraterone (moderate certainty), ADT + enzalutamide (low certainty), ADT + apalutamide (high certainty), and ADT + docetaxel + darolutamide (high certainty) compared with ADT alone. ADT + radiotherapy appeared effective only in low-volume de novo mHSPC. We found a short-term HRQoL decrease lasting 3-6 mo for ADT + docetaxel (moderate certainty) and a potential HRQoL benefit for ADT + abiraterone up to 24 mo of follow-up (moderate certainty) compared with ADT alone. There was no difference in HRQoL for ADT + enzalutamide, ADT + apalutamide, or ADT + radiotherapy over ADT alone (low-high certainty). Grade 3-5 adverse effect rates were increased with all systemic combination treatments. A benefit-harm assessment showed high probabilities (>60%) for a net clinical benefit with ADT + abiraterone, ADT + enzalutamide, and ADT + apalutamide, while ADT + docetaxel and ADT + docetaxel + darolutamide appeared unlikely (<40%) to be beneficial. CONCLUSIONS: Despite substantial survival benefits, no systemic combination treatment showed a clear HRQoL improvement compared with ADT alone. We found evidence for a short-term HRQoL decline with ADT + docetaxel and a higher net clinical benefit with ADT + abiraterone, ADT + apalutamide and ADT + enzalutamide. While individualized decision-making remains important and economic factors need to be considered, the evidence may support a general preference for the combination of ADT with androgen receptor axis-targeted therapies over docetaxel-containing strategies. PATIENT SUMMARY: We assessed different combination treatments for metastatic hormone-sensitive prostate cancer. While survival was better with all systemic combination treatments, there was no clear improvement in health-related quality of life compared with androgen deprivation therapy alone. Novel hormonal combination treatments had a more favorable benefit-harm balance than combination treatments that include chemotherapy.

COVID-19 pandemic restrictions continuously impact on physical activity in adults with cystic fibrosis.

BACKGROUND: We have recently reported reduced physical activity (PA) in people with cystic fibrosis (pwCF) with and without lung transplantation (LTX) during a 6-week stringent lockdown in Switzerland. This follow-up study explores the impact of coronavirus-2019 disease (COVID-19) related pandemic restrictions on individuals' therapy regimens and health-related aspects in pwCF. METHODS: We conducted a cross-sectional web-based national survey in Spring 2021. The survey included questions on daily PA, airway clearance and inhalation therapy, questions on COVID-19-compatible symptoms, diagnostic tests and vaccination status, and enquired health-related aspects covering the pandemic period between March 2020 to April 2021. RESULTS: 193 individuals with CF (53% female; 25% LTX recipients) participated. Among pwCF, 10 reported COVID-19 (n = 2 LTX recipients), two subjects were hospitalized, no invasive ventilation required, no deaths. The clinical course was generally mild. Overall, 46% reported less PA during the pandemic, mostly due to closed fitness facilities (85%), lack of motivation (34%), and changes in daily structures (21%). In contrast, 32/193 (17%) pwCF were able to increase their PA levels: 12 (38%) and 11 (34%) reported undertaking home-based training and outdoor activities more frequently; 6 (19%) reported an increase in routine PA, and another 3 (9%) started new activities. Among pwCF without LTX, 5% and 4% reported to undertake less airway clearance and inhalation therapy, respectively. CONCLUSIONS: Our study reveals unfavorable consequences of COVID-19 pandemic restrictions on PA of pwCF with unknown long-term consequences for their overall physical fitness and lung health. Strategies to overcome this undesirable situation are needed; increased uptake of telehealth PA programs and virtual exercise classes to promote PA participation might be one promising approach along with vaccination of pwCF and their close contacts.

Neoadjuvant Therapy for Resectable Pancreatic Cancer: A New Standard of Care. Pooled Data From 3 Randomized Controlled Trials.

OBJECTIVE: The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome. SUMMARY BACKGROUND DATA: Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations. METHODS: Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards. RESULTS: A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI®) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters. CONCLUSION: Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.

Recommended shielding against COVID-19 impacts physical activity levels in adults with cystic fibrosis.

BACKGROUND: Severe acute respiratory syndrome - coronavirus-2 (SARS-CoV-2) has caused a pandemic threatening the life of people with chronic respiratory diseases including cystic fibrosis (CF). This study was designed to investigate health-related aspects of individuals with CF, with and without lung transplantation (LTX), their communication with their specialist healthcare providers during the pandemic, potential changes in peoples' individual therapy regimes and daily physical activity levels. METHODS: A web-based survey was conducted among Swiss adults with CF with and without LTX, study period from March 16th, 2020 - the day the "extraordinary situation" was officially declared in Switzerland introducing stringent measures protecting the public - until May 16th, 2020. RESULTS: 327 individuals (25% LTX recipients) were included, 45 individuals reported coronavirus-2019 disease (COVID-19) like symptoms. Of 28 subjects tested, only three subjects were tested positive, all with mild symptoms, no hospitalization required. Almost half of the survey respondents (45%) reported undertaking less physical activity during the lockdown, while 79% and 91% of participants reported no change in traditional airway clearance and inhalation therapies, respectively. Distress regarding a potential SARS-CoV-2 infection or worsening of lung disease were no major concerns for subjects. CONCLUSIONS: Our study reveals that the direct impact of SARS-CoV-2 on clinical outcomes of individuals with CF was mild although people with chronic lung diseases like CF are considered a high-risk population; overall, this is reassuring. However, strict lockdown measures substantially affected peoples' physical activity levels, a vital cornerstone of CF therapy; and this is worrisome.

Bronchoalveolar lavage cytokines are of minor value to diagnose complications following lung transplantation.

Early diagnosis and treatment of acute cellular rejection (ACR) may improve long-term outcome for lung transplant recipients (LTRs). Cytokines have become valuable diagnostic tools in many medical fields. The role of bronchoalveolar lavage (BAL) cytokines is of unknown value to diagnose ACR and distinguish rejection from infection. We hypothesized that distinct cytokine patterns obtained by surveillance bronchoscopies during the first year after transplantation are associated with ACR and microbiologic findings. We retrospectively analyzed data from 319 patients undergoing lung transplantation at University Hospital Zurich from 1998 to 2016. We compared levels of IL-6, IL-8, IFN-γ and TNF-α in 747 BAL samples with transbronchial biopsies (TBB) and microbiologic results from surveillance bronchoscopies. We aimed to define reference values that would allow distinction between four specific groups "ACR", "infection", "combined ACR and infection" and "no pathologic process". No definitive pattern was identified. Given the overlap between groups, these four cytokines are not suitable diagnostic markers for ACR or infection after lung transplantation.

BMI-mortality association: shape independent of smoking status but different for chronic lung disease and lung cancer.

Background: Besides smoking, low or high body mass index (BMI) is associated with chronic lung disease (CLD). It is unclear how CLD is associated with BMI, whether smoking interacts with this association, and how the associations differ from the patterns known for lung cancer. Population and Methods: Our population comprised 35,212 individuals aged 14-99, who participated in population-based surveys conducted in 1977-1993 in Switzerland (mortality follow-up until 2014). We categorized smokers into never, former, light, and heavy; and BMI into underweight, normal weight, overweight, and obese. Hazard ratios (HRs) were obtained with multivariable Cox proportional hazards models. Results: CLD mortality was strongly associated with being underweight. This was mainly due to the effect in men (HR 5.04 [2.63-9.66]) and also prevailed in never smokers (HR 1.81 [1.11-3.00]). Obesity was also associated with CLD mortality (HR men: 1.37 [1.01-1.86], women: 1.39 [0.90-2.17]), but not with lung cancer mortality. In line with lung cancer, for CLD, the BMI-mortality association followed the same shape in all smoking categories, suggesting that this association was largely independent of smoking status. Conclusion: The shape of the BMI-mortality association was inversely linear for lung cancer but followed a U-shape for CLD. Further research should examine the potentially protective effect of obesity on lung cancer occurrence and the possibly hazardous impact of underweight on CLD development.

Pulmonary involvement in Fabry disease: effect of plasma globotriaosylsphingosine and time to initiation of enzyme replacement therapy.

INTRODUCTION: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations of GLA gene leading to reduced α-galactosidase activity and resulting in a progressive accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Plasma Lyso-Gb3 levels serve as a disease severity and treatment monitoring marker during enzyme replacement therapy (ERT). METHODS: Adult patients with AFD who had yearly pulmonary function tests between 1999 and 2015 were eligible for this observational study. Primary outcome measures were the change in z-score of forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. Plasma Lyso-Gb3 levels and the age of ERT initiation were investigated for their association with lung function decline. RESULTS: Fifty-three patients (42% male, median (range) age at diagnosis of AFD 34 (6-61) years in men, 34 (13-67) in women) were included. The greatest decrease of FEV1/FVC z-scores was observed in Classic men (-0.048 per year, 95% CI -0.081 to -0.014), compared with the Later-Onset men (+0.013,95% CI -0.055 to 0.082), Classic women (-0.008, 95% CI -0.035 to +0.020) and Later-Onset women (-0.013, 95% CI -0.084 to +0.058). Cigarette smoking (P=0.022) and late ERT initiation (P=0.041) were independently associated with faster FEV1 decline. FEV1/FVC z-score decrease was significantly reduced after initiation of ERT initiation (-0.045 compared with -0.015, P=0.014). Furthermore, there was a trend towards a relevant influence of Lyso-Gb3 (P=0.098) on airflow limitation with age. CONCLUSION: Early ERT initiation seems to preserve pulmonary function. Plasma Lyso-Gb3 is maybe a useful predictor for airflow limitation. Classic men need a closer monitoring of the lung function.

Physical activity and sedentary behavior in preschoolers: a longitudinal assessment of trajectories and determinants.

BACKGROUND: Despite physical activity (PA) being recognized as a critically important factor for good physical and mental health already early in life and throughout the life course, prospective data on activity behavior during the preschool years remains scarce. This study examined trajectories and determinants of levels and change in total PA (TPA), moderate-to-vigorous PA (MVPA) and sedentary behavior (SB) in a representative sample of Swiss preschoolers. METHODS: Data were drawn from the Swiss Preschoolers' Health Study (SPLASHY), a multi-site prospective cohort study including 555 children (53% boys) aged 2-to-6 years at baseline. A follow-up was conducted after 12 months. Activity behavior was measured using accelerometers. Information on 35 potential determinants from different socio-ecological domains was either directly measured or parent-reported. Trajectories of TPA, MVPA and SB over time were described for boys and girls. Linear mixed models were used to investigate factors that predicted levels and change in TPA, MVPA and SB. RESULTS: All children were sufficiently physically active according to published recommendations for preschoolers. Trajectory profiles revealed a marked increase in TPA and MVPA in boys and girls whereas SB remained fairly stable over time. Mixed modeling demonstrated that variables most relevant to determining PA levels were sex, age and activity temperament (all positively associated). Together with gross motor skills, birth weight, family structure (only for TPA) and season (only for MVPA), these factors accounted for 26 and 32% of total variance explained in TPA and MVPA, respectively. Activity temperament emerged as the strongest determinant of SB (negative association) and explained with sex, season and family structure 20% of total variance in SB. The presence of older siblings was the only factor that predicted change in PA over time. CONCLUSIONS: In this healthy physically active cohort of preschoolers, non-modifiable individual-level factors had the greatest influence on PA. The limited success of this and previous studies to identify modifiable determinants and the finding that most preschoolers were sufficiently active suggest that future attempts should provide insights into how preschoolers' activity levels can be maintained and fostered to prevent subsequent harmful declines attributable, amongst others, to educational transitions. Thus, good-quality longitudinal studies are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41045021 (date of registration: 21.03.14).

Prognostic value of MIB-1 proliferation index in solitary fibrous tumors of the pleura implemented in a new score - a multicenter study.

BACKGROUND: Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, 10-25% of patients suffer from recurrence or metastatic disease. Several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators. METHODS: In this multicenter study, we collected clinical data and formalin-fixed and paraffin-embedded (FFPE) tissue blocks of patients with histologically proven SFTP which had been surgically resected between 2000 und 2015. After systematic and extensive IHC staining on tissue microarrays, the results were analyzed and compared to histomorphological and clinical data for their possible prognostic value. RESULTS: In total, 78 patients (mean age 61 ± 11 years) were included. Of these, 9 patients (11%) had an adverse outcome including SFTP recurrence (n = 6) or SFTP-related death (n = 3). Mean overall survival was 172 ± 13 months. 1 and 10-year event-free survival rates were 99% and 93%. In the multivariable analysis only MIB-1 proliferation index (Ki-67) ≥10% (HR 12.3, CI 1.1-139.5, p = 0.043), ≥4 mitoses per 10 high power fields (HR 36.5, CI 1.2-1103.7, p = 0.039) and tumor size larger than 10 cm (HR 81.8, CI 1.7-4016.8, p = 0.027) were independently associated with adverse outcome. CONCLUSION: A high proliferation rate by MIB-1 IHC was associated with impaired outcome. Upon this, we established a new score using mitosis, necrosis, size of the tumor and MIB-1, which performed better than the traditional scores in our data set. This prognostic score could help to better evaluate outcome of SFTP, but requires external validation.

Commonly Used Patient-Reported Outcomes Do Not Improve Prediction of COPD Exacerbations: A Multicenter 4½ Year Prospective Cohort Study.

BACKGROUND: Several cross-sectional and short-term studies suggest that patient-reported outcomes (PROs) may be useful to help predict COPD exacerbations, but evidence from long-term prospective cohort studies is lacking. Our aim was to assess if PROs add to the prediction of exacerbations. METHODS: Four hundred eight primary care patients with COPD participated in the multicenter prospective International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts (ICE COLD ERIC) study. PROs included the Chronic Respiratory Disease Questionnaire, the Hospital Anxiety and Depression Scale, the Feeling Thermometer, and the LASA Physical Activity Questionnaire (LAPAQ). Exacerbations during 4½ years were adjudicated by experts. We used negative binomial regression to assess the association between PROs and exacerbations while considering age, sex, airflow obstruction, previous exacerbations, and smoking status. We then assessed if adding PROs improved the predictive properties of widely used indices. RESULTS: Lower levels of dyspnea, fatigue, and anxiety and higher levels of physical activity were associated with a lower risk of exacerbations (adjusted incidence rate ratio [IRR], 0.90; 95% CI, 0.84-0.97; P = .01; IRR, 0.93; 95% CI, 0.86-1.00; P = .04; IRR, 1.03; 95% CI, 1.00-1.06; P = .03; IRR, 0.93; 95% CI, 0.87-0.99; P = .04, respectively). The best prediction was when LAPAQ was added to the BMI, airflow obstruction, dyspnea, and previous exacerbations (BODEx) index (area under the curve Δ+0.02, from 0.72-0.74). However, this increase was not clinically relevant (net reclassification improvement, 0.03; 95% CI, -0.03 to 0.08). CONCLUSIONS: Some domains of PROs are independently associated with exacerbations but do not lead to clearly improved prediction when added to established indices to predict exacerbations. There is still much room for improvement in the prediction of exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00706602.

Long-term follow-up of pulmonary function in Fabry disease: A bi-center observational study.

INTRODUCTION: Fabry disease (FD) is a lysosomal storage disorder leading to decreased α-galactosidase A enzyme activity and subsequent abnormal accumulation of glycosphingolipids in various organs. Although histological evidence of lung involvement has been demonstrated, the functional impact of these changes is less clear. MATERIALS AND METHODS: Adult patients with FD who had yearly pulmonary function tests (PFT) at two centers from 1999 thru 2015 were eligible for this observational study. Primary outcome measures were the change in forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. As secondary outcome we investigated sex, smoking, enzyme replacement therapy (ERT), residual enzyme activity, and Mainz Severity Score Index as possible predictors. RESULTS: 95 patients (41% male, 38.2 ± 14.5 years) were included. The overall prevalence of bronchial obstruction (BO, (FEV1/FVC < 70%)) was 46%, with male sex, age and smoking as significant predictors. FEV1 decreased 29 ml per year (95% CI -36, -22 ml, p<0.0001). FEV1 decline was significantly higher in males (p = 0.009) and in patients on ERT (p = 0.004). Conclusion: Pulmonary involvement seems to be a relevant manifestation of Fabry disease, and routine PFTs should therefore be included in the multidisciplinary follow-up of these patients.

Body height and mortality - mortality follow-up of four Swiss surveys.

BACKGROUND: Adult body height is largely determined by genetics, but also by dietary factors, which in turn depend on socioeconomic status and lifestyle. We examined the association between adult body height and mortality in Switzerland, a country with three main language regions with different cultural background. METHODS: We included 16,831 men and 18,654 women, who participated in Swiss population-based health surveys conducted 1977-1993 and who were followed up until end of 2008. Multivariable Cox proportional hazards models were computed to examine the association of body height with overall, cardiovascular, and cancer mortality. RESULTS: We observed a positive association between adult body height and all-cause mortality in women (HR=1.34, 95% CI 1.10-1.62, tallest vs. average women). In men, mortality risk decreased with increasing height, with shortest men tending to have higher (1.06, 0.94-1.19) and tallest men a lower (0.94, 0.77-1.14) risk compared with men of average height (p-trend 0.0001). Body height was associated with cancer mortality in women, such that tallest women had a higher risk of dying from cancer than women of average height (1.37, 1.02-1.84), but there was no such association in men (0.95, 0.69-1.30). In both sexes, height was not associated with cardiovascular mortality in a statistically significant manner. CONCLUSION: Our study does not support an inverse association of body height with all-cause mortality. On the contrary, our data suggests a higher overall risk in taller women, mainly driven by a positive association between body height and cancer mortality.

Follow-up practices for high-grade extremity Osteosarcoma.

BACKGROUND: The optimal conduct of follow-up (FU) of patients with osteosarcoma is uncertain. In the absence of any formal validation of optimal timing and method of surveillance, guidance is provided by oncology societies' recommendations. FU is designed to detect either local recurrence or metastatic disease at a time when early treatment is still possible and might be effective. METHODS: We performed a retrospective analysis of 101 patients with high-grade extremity osteosarcoma in a single centre. Chest x-ray (CXR) was used as routine surveillance method; however patients with initial lung metastases or previous suspicious findings had computed tomography (CT) scans. RESULTS: With a median FU time of 30.7 months 34 patients relapsed. Relapse-free survival after 5 years was 61% (CI 52%; 73%), late relapses occurred in only two patients between 2 and 5 years of FU. Twenty-five of the 34 relapses were detected at routine FU appointments. All 8 local recurrences were noted clinically. Twenty-two patients had metastases confined to the lungs, either detected on CXR or CT. Thirty-two percent of patients with lung metastases only were salvaged successfully. CONCLUSIONS: Routine FU in high-grade osteosarcoma results in clinical detection of local relapse, and detection of lung metastases by CXR at a time when metastatectomy is possible. The optimal time interval for FU appointments is not known, however we recommend more frequent surveillance visits during the two years after treatment. We hypothesize that routine CT scans are not required and propose CXR for detection of lung metastases.