[1] D Faeh, M Kaufmann, S R Haile, and M Bopp for the Swiss National Cohort Study Group. BMI-mortality-association: shape independent of smoking status but different for chronic lung disease and lung cancer. International Journal of Chronic Obstructive Pulmonary Disease, 13:1851 -- 1855, 2018. [ bib | DOI ]
Besides smoking, low or high 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 differs from the patterns known for lung cancer. Our population comprised 35,212 individuals aged 14-99, who participated in population-based surveys conducted 1977-1993 in Switzerland (mortality-follow-up until 2014). We categorized smokers into never, former, light, heavy; BMI into underweight, normal weight, overweight, obese. Hazard Ratios (HR) were obtained with multivariable Cox proportional hazards models. CLD mortality was strongly associated with 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. The shape of the BMI-mortality-association was inversely linear for lung cancer but followed a U-shape for CLD. Further research should examine This suggests a potentially protective effect of obesity on lung cancer occurrence and the possibly hazardous impact of underweight on CLD development.

[2] D P Franzen, S R Haile, D C Kasper, T P Mechtler, A J Flammer, P A Krayenbuehl, and A Nowak. Pulmonary involvement in Fabry disease: Effect of plasma globotriaosylsphingosine and time to initiation of enzyme replacement therapy. BMJ Open Respiratory Research, 5(1), 2018. [ bib | DOI ]
Rationale: Anderson-Fabry disease (AFD) is 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). Objectives. We investigated the predictors of lung disease progression in AFD. Methods: Adult patients with AFD who have yearly pulmonary function tests between 1999 and 2015 were eligible for this observational study. Measurements. 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. Main Results: Fifty-three patients (42% male, median age at diagnosis of AFD 34 [6-61] years in males, 34 [13-67] in females) were included. The greatest decrease of FEV1/FVC z-scores was observed in Classic males (-0.048 per year, 95% CI (-0.081, -0.014)). For the Later-Onset males (+0.013, (-0.055, 0.082)). For the Classic (-0.008 (-0.035, +0.020)) and Later-Onset females (-0.013, (-0.084, +0.058)), there was no or less relevant decrease. Cigarette smoking (p=0.037) and late ERT initiation (p=0.028) were independently associated with faster FEV1 decline. There was a trend towards a relevant influence of Lyso-Gb3 (p=0.09) on airflow limitation with age. Conclusion: Early ERT initiation seems to preserve pulmonary function. Plasma Lyso-Gb3 could be useful as predictor for airflow limitation. Classic males need a closer monitoring of the lung function.

[3] B Guerra, S R Haile, B Lamprecht, A S Ramírez, P Martinez-Camblor, B Kaiser, I Alfageme, P Almagro, C Casanova, C Esteban-González, J J Soler-Cataluña, J P de Torres, M Miravitlles, B R Celli, J M Marin, G ter Riet, P Sobradillo-Ecenarro, P Lange, J Garcia-Aymerich, J M Antó-Boqué, A M Turner, M K Han, A Langhammer, L Leivseth, P Bakke, A Johannessen, T Oga, B Cosío, J Ancochea-Bermúdez, A Echazarreta, N Roche, P-R Burgel, D D Sin, J B Soriano, and M A Puhan for the 3CIA collaboration. Large-scale external validation and comparison of prognostic models: An application to chronic obstructive pulmonary disease. BMC Medicine, 16(33), 2018. [ bib | DOI ]
Background: External validations and comparisons of prognostic models or scores are a pre-requisite for their use in routine clinical care but lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD.

Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment (3CIA) consortium, corresponding to primary, secondary and tertiary care in Europe, the Americas and Japan. They include globally 15762 patients with COPD (1871 deaths and 42203 person-years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity and inconsistency and provided a performance ranking of the prognostic scores.

Results: Depending on data availability, between 2 and 9 prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea and exercise capacity) had a median AUC of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea and airflow obstruction) showed the best performance for predicting mortality (difference AUC_ADO - AUC_BODE = 0.015 [95% confidence interval (CI) = -0.002 to 0.032; p = 0.08) followed by the updated BODE (AUC_BODE updated - AUC_BODE = 0.008 [95% CI = -0.005 to +0.022; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small and we did not identify any local or global inconsistency.

Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any the medical field to identify the best scores, possibly paving the way for stratified medicine, public health and research.

Keywords: COPD, prognostic scores, large-scale external validation, performance comparison, network meta-analysis
[4] E A Schmutz, S R Haile, C S Leeger-Aschmann, T H Kakebeeke, A E Zysset, N Messerli-Bürgy, K Stülb, A Arhab, A H Meyer, S Munsch, J J Puder, O G Jenni, and S Kriemler. Physical activity and sedentary behavior in preschoolers: a longitudinal assessment of trajectories and determinants. International Journal of Behavioral Nutrition and Physical Activity, 15(35), 2018. [ bib | DOI ]
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 two-to-six 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.

[5] A Stöberl, E I Schwarz, S R Haile, C Turnbull, V Rossi, J Stradling, and M Kohler. Night-to-night variability of obstructive sleep apnoea. Journal of Sleep Research, 26:782--788, December 2017. [ bib | DOI ]
One night of a sleep study is the standard for diagnosis and exclusion of obstructive sleep apnoea (OSA). Single testing requires high sensitivity of the test method and a stable disease of interest to warrant a low rate of false negative tests. OSA is diagnosed and graded by conventional thresholds of apnoeas and hypopnoeas per hour of sleep and treatment is usually initiated in the presence of symptoms. The aim of this study was to assess night-to-night variability of OSA to reassess the current practice. 77 patients previously diagnosed with OSA, randomised to continuous positive airway pressure (CPAP) withdrawal within four trials, performed nightly pulse-oximetry over two weeks while off CPAP. The main outcome of interest was the coefficient of variation (CV) of the oxygen desaturation index (ODI) marking night-to-night variability in OSA. OSA was categorised according to conventional thresholds using ODI (no OSA: <5/h, mild 5-15/h, moderate 15-30/h and severe >30/h). High night-to-night variability of OSA was evidenced by a CV of ODI of 31.1% (SD16.5). Differences in ODI of >10/h between nights were found in 84.4% and shifts in OSA severity-category in 77.9% of patients. The probability of missing moderate OSA was up to 60%. Variability was higher in less severe OSA. OSA shows a considerable night-to-night variability. Single-night diagnostic sleep studies are prone to miscategorise OSA if arbitrary thresholds are used. Thus treatment decisions should be based less on the conventional derivatives from sleep studies, especially in patients with less severe OSA.

[6] S Rohrmann, S Haile, K Staub, M Bopp, and D Fäh. Body height and mortality - mortality follow-up of four Swiss surveys. Preventive Medicine, 101:67–71, August 2017. [ bib | DOI ]
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.

[7] D P Franzen, A Nowak, S R Haile, D Mottet, M Bonani, O Dormond, M Kohler, P A Krayenbuehl, and F Barbey. Long-term follow-up of pulmonary function in Fabry disease: a bi-center observational study. PLOS ONE, 12(7):1--15, July 2017. [ bib | DOI ]
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. Adult patients with FD who had yearly pulmonary function tests (PFT) at two centres 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. 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). 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, since early treatment initiation may prevent pulmonary disease progression.

[8] S R Haile, B Guerra, J B Soriano, and M A Puhan for the 3CIA collaboration. Multiple score comparison: A network meta-analysis approach to comparison and external validation of prognostic scores. BMC Medical Research Methodology, 17(172), 2017. [ bib | DOI ]
Background: Prediction models and prognostic scores have been increasingly popular in both clinical practice and clinical research settings, for example to aid in risk-based decision making or control for confounding. In many medical fields, a large number of prognostic scores are available, but practitioners may find it difficult to choose between them due to lack of external validation as well as lack of comparisons between them.

Methods: Borrowing methodology from network meta-analysis, we describe an approach to Multiple Score Comparison meta-analysis (MSC) which permits concurrent external validation and comparisons of prognostic scores using individual patient data (IPD) arising from a large-scale international collaboration. We describe the challenges in adapting network meta-analysis to the MSC setting, for instance the need to explicitly include correlations between the scores on a cohort level, and how to deal with many multi-score studies. We propose first using IPD to make cohort-level aggregate discrimination or calibration scores, comparing all to a common comparator. Then, standard network meta-analysis techniques can be applied, taking care to consider correlation structures in cohorts with multiple scores. Transitivity, consistency and heterogeneity are also examined.

Results: We provide a clinical application, comparing prognostic scores for 3-year mortality in patients with chronic obstructive pulmonary disease using data from a large-scale collaborative initiative. We focus on the discriminative properties of the prognostic scores. Our results show clear differences in performance, with ADO and eBODE showing higher discrimination with respect to mortality than other considered scores. The assumptions of transitivity and local and global consistency were not violated. Heterogeneity was small.

Conclusions: We applied a network meta-analytic methodology to externally validate and concurrently compare the prognostic properties of clinical scores. Our large-scale external validation indicates that the scores with the best discriminative properties to predict 3 year mortality in patients with COPD are ADO and eBODE.

Keywords: prognostic scores, external validation, multiple score comparison, chronic obstructive pulmonary disease
[9] C F Clarenbach, N A Sievi, S R Haile, T Brack, H Brutsche, M Frey, S Irani, J D Leuppi, R Thurnheer, and M Kohler. Determinants of annual change in physical activity in COPD. Respirology, 22:1133--39, 2017. [ bib | DOI ]
BACKGROUND AND OBJECTIVE: Daily physical activity (PA) is reduced in patients with COPD. Previous cross-sectional analyses indicate various predictors for a low level of PA including airway obstruction, exacerbations and co-morbidities. However, information from longitudinal studies evaluating PA in the context of disease progression, survival and co-morbidities is scant.

METHODS: In a heterogeneous cohort of COPD patients, we annually assessed the number of steps per day over 1 week and potential determinants including lung function, exacerbations and co-morbidities. Univariable and multivariable mixed effect models were used to investigate associations between the change in steps per day (dependent variable) and possible predictors and their annual changes.

RESULTS: A total of 177 COPD patients (46% GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 1/2, 38% stage 3 and 16% stage 4) with a mean (min/max) follow-up time of 2.7 (1/5) years were annually assessed. The number of steps per day decreased significantly over time (P < 0.001) with a mean annual change of -508 steps. The decrease in activity was significantly associated with forced expiratory volume in 1 s (FEV1 ) % predicted (P = 0.020) but not with annual changes in FEV1 . Hyperinflation, exacerbations, co-morbidities and their annual changes, and survival did not significantly affect change in PA.

CONCLUSION: COPD patients have a substantial decrease of PA over time. This decrease seems to be determined by the degree of airflow limitation. However, patients with a greater annual decline in lung function did not show a greater decrease in PA. The rate of decline in PA did not differ between survivors and non-survivors in this cohort.

[10] M Diebold, A Soltermann, S Hottinger, S R Haile, L Bubendorf, P Komminoth, W Jochum, R Grobholz, D Theegarten, S Berezowska, K Darwiche, F Özkan, M Kohler, and D P Franzen. Prognostic value of MIB-1 proliferation index in solitary fibrous tumors of the pleura implemented in a new score – a multicenter study. BMC Respiratory Research, 18(210), 2017. [ bib | DOI ]
Introduction: Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, up to 30% of patients suffer from recurrence or metastatic disease. Therefore, several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators.

Methods: In this prospective 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 histo-morphological and clinical data for their possible predictive 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 200 7.7 months. 1-, 5-, 10-year event-free survival rates were 99%, 93% and 62%, respectively. 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.

Conclusions: A high proliferation rate assessed by MIB-1 IHC was associated with impaired outcome. Upon this, we constructed a new score using four variables including MIB-1, which performed better than the traditional scores in our data. This prognostic score could help to better predict outcome of SFTP, but requires external validation.

[11] H Joswig, S R Haile, G Hildebrandt, and MN Stienen. Residents learning curve of lumbar transforaminal epidural steroid injections. Journal of Neurological Surgery (Part A), 78(05):460 -- 466, 2017. [ bib | DOI ]
Background and Study Aims: There is a paucity of literature on beginners’ training and on the connection between patient safety for transforaminal epidural steroid injections (TFESI). It is the aim of this study to retrospectively assess the learning curves and associated complications of neurosurgery residents previously never exposed to TFESI and to compare them to experienced board-certified faculty neurosurgeons (BCFN).

Material and Methods: Procedure time in minutes (min), dose-area-product (DAP) in cGy*cm2, periprocedural observations and complications in n=354 TFESI for radicular pain secondary to lumbar disc herniation or lumbar spinal stenosis were extracted from operative notes and the electronic infiltration logbook in the per-injection format. Learning curves for residents (n=238) and BCFN (n=116) TFESI in terms of procedure time and DAP were estimated using monotone regression.

Results: Residents TFESI procedure time and DAP reached BCFN level (4.7 min and 140.2 Gy*cm2) after 67 and 68 cases, respectively. Residents TFESI were unsuccessful in 1.7%, mostly for severe obesity and hypertrophied facet joints, but no severe complications were noted. Obesity, however, did not result in increased procedure times or radiation exposure in general. Residents were faster and required less fluoroscopy in TFESI of the upper lumbar nerve roots than for L5 or S1 in particular.

Conclusion: The residents learning curve for TFESI in terms of procedure time and radiation exposure can be overcome safely after less than 70 TFESI. An outcome analysis correlating to the interventionalist’s training level would be worth investigating in future studies.

[12] R B Mueller, N Reshiti, T Kaegi, A Finckh, S R Haile, H Schulze-Koops, Ml Schiff, M Spaeth, and J von Kempis on behalf of the SCQM physicians. Does addition of glucocortiocids to the initial therapy influence the later course of the disease in patients with early RA? results from the swiss prospective observational registry (SCQM). Clinical Rheumatology, 36(1):59--66, 2017. [ bib | DOI ]
The main goal of this study was to analyse whether initial addition of glucocorticoid to DMARD therapy influences the long-term course of the disease in patients with early rheumatoid arthritis. All patients from the Swiss RA cohort SCQM with recent-onset arthritis (disease duration <=1 year) were analysed. The exposure of interest was the use of glucocorticoids (GCs) at baseline. As primary outcome, we considered clinical and radiographic disease progression, assessed by the disease activity (disease activity score, DAS-28), function (health assessment questionnaire disability index, HAQ-DI) and structural joint damage (Ratingen erosion score). The baseline disease characteristics were compared using standard descriptive statistics. The effects of initial GC use on disease progression during follow-up were estimated using linear mixed models with random slope and random intercept, adjusted for potential confounders. In total, 592 patients with early disease were available, with 4.3 years of follow-up (average). Of these, 363 were initially treated with glucocorticoids (GC patients) and 228 were not (no-GC patients). DAS-28 (4.6 vs. 4.3, p = 0.01) and the HAQ-DI (0.94 vs. 0.82, p = 0.01) were higher at baseline in GC patients, while other prognostic factors were balanced at baseline. Neither the change of DAS-28, of HAQ-DI nor of the development of joint erosions differed between the two groups during follow-up. Escalation of treatment employing biologics was documented in 18.0% of the no-GC patients and 27.3% of the GC patients (p < 0.01). In this cohort, patients with early RA initially treated with GCs had higher measures of disease activity at baseline in comparison to no-GC patients. Despite a similar course of the disease in GC versus non-GC patients, the higher escalation rate to biologic agents in GC patients may reflect a disease less responsive to therapy in these patients. These data suggest that GC use as part of the initial therapeutic strategy in early RA may prevent a more severe course of the disease in patients with higher clinical disease measures at the start of therapy.

[13] A Strassmann, A Frei, S R Haile, G ter Riet, and M Puhan. Commonly used patient-reported outcomes do not improve prediction of COPD exacerbations - a multicenter 4.5 year prospective cohort study. CHEST, 152:1179--1187, 2017. [ bib | DOI ]
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 missing. Our aim was to assess if PROs add to the prediction of exacerbations.

Methods: 408 primary care COPD patients participated in the multicenter prospective ICE COLD ERIC cohort. 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 4.5 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 activities were associated with lower risk of experiencing exacerbations (adjusted incidence rate ratio 0.90, 95% CI 0.84, 0.97, p=.01; 0.93, CI 0.86, 1.00, p=0.04; 1.03, CI 1.00, 1.06, p=.03; 0.93, CI 0.87, 0.99, p=.04). The best prediction was when LAPAQ was added to the BODEx index (area under curve ∆+0.02, from 0.72 to 0.74). However, this increase was not clinically relevant (net reclassification improvement 0.03, 95% CI -0.03, 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.

[14] R Maquieira, S K Haerle, G F Huber, A Soltermann, S R Haile, S J Stoeckli, and M A Broglie. No benefit for regional control and survival by planned neck dissection in primary irradiated oropharyngeal cancer irrespective of p16 expression. European Archives of Oto-Rhino-Laryngology, 273:1841--1848, July 2016. [ bib | DOI ]
The aim of the study was to assess regional control and survival in primary irradiated oropharyngeal cancer patients with advanced neck disease (≥cN2a) receiving planned neck dissection (PND) irrespective of the nodal response compared to salvage neck dissection (SND) in case of regional persistence or reccurence in relation to tumoral p16 overexpression. 96 consecutive patients treated at the University Hospital of Zurich, Switzerland were included. Tissue microarray-based scoring of p16 expression was obtained. 5 years overall (OS) and disease-specific survival (DSS) in the PND and SND cohort were 70 vs. 57 % (p = 0.20) and 80 vs. 65 % (p = 0.14), respectively. Regional control in PND and SND achieved 95 vs. 87 % (p = 0.29), respectively. There was no statistically significant impact of neck treatment (PND vs. SND) on regional control or survival among patients with p16-negative tumors (5 years OS 59 vs. 50 %, p = 0.66; 5 years DSS 59 vs. 57 %, p = 0.89) nor among patients with p16-positive tumors (5 years OS 84 vs. 67 %, p = 0.21; 5 years DSS 95 vs. 81 %, p = 0.24). The type of neck dissection after primary intensity-modulated radiotherapy (IMRT) had no impact on regional control and survival even in human papillomavirus (HPV)-associated disease. Therefore we are convinced that based on the accuracy of newer diagnostic modalities the surveillance of a radiologically negative neck after primary chemoradiation (CRT) is oncologically safe irrespective of p16 expression of the tumor.

Keywords: Oropharyngeal squamous cell carcinoma; Planned neck dissection; Salvage neck dissection; p16 expression; Regional tumor control; Survival
[15] S R Haile, J-H Jeong, X Chen, and Y Cheng. A 3-parameter Gompertz distribution for survival data with competing risks, with an application to breast cancer data. Journal of Applied Statistics, 43:2239--2253, 2016. [ bib | DOI ]
The cumulative incidence function is of great importance in the analysis of survival data when competing risks are present. Parametric modeling of such functions, which are by nature improper, suggests the use of improper distributions. One frequently used improper distribution is that of Gompertz, which captures only monotone hazard shapes. In some applications, however, cause-specific hazard estimates have been observed with unimodal shapes. An extension to the Gompertz distribution is presented which can capture unimodal as well as monotone hazard shapes. Important properties of the proposed distribution are discussed, and the proposed distribution is used to analyse survival data from a breast cancer clinical trial.

Keywords: Competing Risks; Cumulative incidence function; Improper distribution; Subdistribution Hazards; Parametric modeling; Survival analysis
[16] H Joswig, H Richter, S R Haile, G Hildebrandt, and J-Y Fournier. Introducing interlaminar full-endoscopic lumbar diskectomy: A critical analysis of complications, recurrence rates, and outcome in view of two spinal surgeons’ learning curves. Journal of Neurological Surgery - Part A, 77(05):406--415, 2016. [ bib | DOI ]
Background and Study Objective: Interlaminar full-endoscopic diskectomy is a mini- mally invasive surgical alternative to microdiskectomy for the treatment of lumbar disk herniation. The authors analyze their surgical results and learning curves during and after the introductory phase of this surgical technique. Patients and Methods: We present a case review of 76 patients operated on using interlaminar full-endoscopic diskectomy. We retrospectively analyzed two spinal sur- geons’ learning curves in terms of operation time with respect to intraoperative blood loss, conversion rates, complications, infections, length of hospitalization, need for rehabilitation, recurrence rates, pain intensity, and opioid use. Patients’ functional status and Health-related Quality of Life were assessed by follow-up questionnaires for 47 patients, using the North American Spine Society Score and the Short Form 12 in addition to long-term pain intensity, work capacity, and patient satisfaction with the operation. Results: A steady state of the learning curve (operation time) of an experienced spinal surgeon was reached after 40 cases. Supervision by a more experienced surgeon can shorten the learning curve. The rate of conversions (10%), complications (5%), and recurrent lumbar disk herniations (28%) did not negatively affect the long-term outcome in patients operated on before and after the learning phase. Patient satisfac- tion was high. Conclusions: The rate of conversions, complications, and recurrent lumbar disk herniations compared with microdiskectomy combined with the challenging learning curve should be considered before surgeons adopt this procedure. Supervision by an endoscopically experienced spinal surgeon during the introductory phase is highly advisable.

[17] P M Putora, D Engeler, S R Haile, N Graf, K Buchauer, H P Schmid, and L Plasswilm. Erectile function following brachytherapy, external beam radiotherapy, or radical prostatectomy in prostate cancer patients. Strahlentherapie und Onkologie, 192(3):182--189, 2016. [ bib | DOI ]
For localized prostate cancer, treatment options include external beam radiotherapy (EBRT), radical prostatectomy (RP), and brachytherapy (BT). Erectile dysfunction (ED) is a common side-effect. Our aim was to evaluate penile erectile function (EF) before and after BT, EBRT, or RP using a validated self-administered quality-of-life survey from a prospective registry.

[18] C Rothermundt, BM Seddon, P Dileo, SJ Strauss, J Coleman, TW Briggs, SR Haile, and JS Whelan. Follow-up practices for high-grade extremity osteosarcoma. BMC Cancer, 16(1), 2016. [ bib | DOI ]
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.

[19] S Denoth, M A Broglie, S K Haerle, G F Huber, S R Haile, A Soltermann, W Jochum, and S J Stoeckli. Histopathological mapping of metastatic tumor cells in sentinel lymph nodes of oral and oropharyngeal squamous cell carcinomas. Head and Neck, 37:1477--1482, October 2015. [ bib | DOI ]
Histopathologic protocols for SLNs are designed to provide maximum information about the potential presence of metastases and minimizing the risk of sampling error. The aim of our study was to assess the 3D-distribution of metastatic tumor cells within SLNs and to develop recommendations for time- and cost-efficient histopathologic work-up. For exact measurement of occult metastases an ultra-high resolution image scanning technology was used to create digital images from the microscopic glass slides and the digital images were examined with a virtual microscope. The x-axis described the maximum diameter right-angled to the y-axis. The y-axis expressed the distance between the afferent and efferent pole and the z-axis was reflecting the sectional plane. Micrometastases were located almost in the middle of the x-axis, closer to the inlet and almost in the center of the z-axis. Using the current standardized protocol for histopathologic work-up, in our cohort 35% of the micrometastases were found by dividing the SLN into two blocks. By step sectioning at 150μm intervals 60% of micrometastases were found with a second, 70% with a third and 90% with a fourth slice. In 2/26 of SLNs (8%) micrometastases were only found by cutting the entire lymph node. Most of micrometastases are located closer to the inlet of a SLN. The current protocol for SLN evaluation is therefore reasonable. On the other hand the distribution of metastases is not fully predictable and only complete step sectioning of the SLN does allow the identification of all occult disease.

[20] D C Engel, A Ferrari, A-J Tasman, R Schmid, R Schindel, S R Haile, L Mariani, and J-Y Fournier. A basic model for training of microscopic and endoscopic transsphenoidal pituitary surgery: the egghead. Acta Neurochirurgica, 157:1771--7, October 2015. [ bib | DOI ]
Background: Transsphenoidal endoscopic surgery has gained popularity in the last 2 decades and is becoming a standard technique for resection of pituitary adenomas. In contrast to their ENT colleagues, neurosurgical residents have practically no endoscopic experience when they reach the training stage for transsphenoidal procedures. We have developed an affordable method for repetitive training in endoscopic (and microscopic) work in a narrow channel, allowing training of the basic movements needed for resection of pituitary adenoma. Methods: In collaboration with colleagues in the ENT Department, Cantonal Hospital St. Gall, and the Technical University of Zurich, a three-dimensional model of the nasal cavity was developed and patented. The Egghead model consists of a 3D synthetic reconstruction of the head nasal cavity and sphenoid sinus. A boiled egg represents the sella. For validation, 17 neurosurgical residents from the Department of Neurosurgery, University Hospital of Basel, and Department of Neurosurgery, Cantonal Hospital of St. Gall, St. Gall, Switzerland, and two experts performed a standardized procedure mimicking a transsphenoidal pituitary procedure by dissecting a corridor to the egg yolk and resecting it, respecting the surrounding egg white. This procedure was performed under both microscopic and video-endoscopic visualization. A score for the precision and speed of the surgical performance was developed and used. Results: The model allows repetitive training of the resection of the egg yolk under sparing of the egg white after careful opening of the shell. The validation data showed a steeper learning curve using the endoscopic technique than performing the same task using the microscope. After three repetitions, the quality of resection was better with the endoscopic technique. Conclusions: Our model, the Egghead, is affordable, offers tactile feedback and allows infinite repetitions in basic training for pituitary surgery. It can be used for training of advanced neurosurgical residents, who thus far have very few possibilities of acquiring endoscopic experience.

[21] R Frei, S R Haile, M Mütsch, and S Rohrmann. Relationship of serum vitamin D concentrations and allostatic load as a measure of cumulative biological risk among the US population: a cross-sectional study. PLOS ONE, 10(10), October 2015. [ bib | DOI ]
Introduction: The allostatic load (AL) index is a multi-systemic measure of physiologic dysregulation known to be associated with chronic exposure to stress and adverse health outcomes. We examined the relationship between AL and serum 25-hydroxyvitamin D (25(OH)D) concentration in non-institutionalized US adults. Methods: Data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–94) were used to calculate two versions of AL including 9 biomarkers and another two with 14 biomarkers (systolic and diastolic blood pressure, pulse rate, serum cholesterol, serum HDL-cholesterol, glycated hemoglobin, sex-specific waist-to-hip ratio, serum albumin, and serum C-reactive protein for AL1, and, additionally body mass index, serum triglyceride, serum creatinine, and serum herpes I & II antibodies for AL2), each set defined by predefined cut-offs or by quartiles. Serum vitamin D concentration was ranked into quartiles. Logistic regression, Poisson regression and linear regression were used to examine the association of serum 25(OH)D concentrations on AL, after adjusting for biological, physiological, socioeconomic, lifestyle, and health variables. Results: Odds Ratios (OR) for high AL of the lowest 25(OH)D serum quartile were between 1.45 (95% CI: 1.28, 1.67) and 1.79 (95% CI: 1.39, 2.32) for the fully adjusted model, depending on AL version. Inverse relationships between vitamin D serum concentrations were observed for all AL versions and every adjustment. This relationship was consistent after stratification by sex, age or ethnic background. Sensitivity to low 25(OH)D concentrations was highest among the youngest group (20–39 years) with an OR of 2.11 (95% CI: 1.63, 2.73) for the lowest vitamin D quartile Q1. Conclusions: Vitamin D had a consistent and statistically significant inverse association with all tested models of high AL, which remained consistent after adjusting for biological, socioeconomic, lifestyle and health variables. Our study adds evidence linking low 25(OH)D concentrations with poorer health, further-reaching than bone health.

[22] M Kraus, J Bader, P P. Geurink, E S. Weyburne, A C. Mirabella, T Silzle, T B. Shabaneh, W A. van der Linden, G de Bruin, S R. Haile, E van Rooden, C Appenzeller, N Li, A F. Kisselev, H Overkleeft, and C Driessen. The novel β2-selective proteasome inhibitor lu-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells. Haematologica, 100(10):1350--1360, October 2015. [ bib | DOI ]
Proteasome inhibitor resistance is a challenge for myeloma therapy. Bortezomib targets the β5 and β1 activity, but not the β2 activity of the proteasome. Bortezomib-resistant myeloma cells downregulate the activation status of the unfolded protein response, and upregulate β2 pro-teasome activity. To improve proteasome inhibition in bortezomib-resistant myeloma and to achieve more efficient activation of the unfolded protein response, we have developed LU-102, a selective inhibitor of the β2 proteasome activity. LU-102 inhibited the β2 activity in intact myeloma cells at low micromolar concentrations without relevant co-inhibition of β1 and β5 proteasome subunits. In pro-teasome inhibitor-resistant myeloma cells, significantly more potent proteasome inhibition was achieved by bortezomib or carfilzomib in combination with LU-102, compared to bortezomib/carfilzomib alone, resulting in highly synergistic cytotoxic activity of the drug combination via endoplasmatic reticulum stress induced apoptosis. Combining bortezomib/carfilzomib with LU-102 significantly prolonged proteasome inhibition and increased activation of the unfolded protein response and IRE1-1α± activity. IRE1-'alpha± has recently been shown to control myeloma cell differentiation and bortezomib sensitivity (Leung-Hagesteijn, Cancer Cell 24:3, 289-304). Thus, β2-selective proteasome inhibition by LU-102 in combination with bortezomib or carfilzomib re-sults in synergistic proteasome inhibition, activation of the unfolded protein response, and cytotoxicity, and overcomes bortezomib/carfilzomib resistance in myeloma cells in vitro.

[23] R B Mueller, J von Kempis, S R Haile, and M H Schiff. Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real-world data from the St. Gallen cohort. Seminars in Arthritis and Rheumatism, 45:28--34, August 2015. [ bib | DOI ]
[24] D Abt, E Warzinek, HP Schmid, SR Haile, and DS Engeler. Influence of patient education on morbidity caused by ureteral stents. International Journal of Urology, 22:679--683, July 2015. [ bib | DOI ]
OBJECTIVES: To investigate the influence of patient education on symptoms and problems caused by ureteral stents. METHODS: The German version of the Ureteral Stent Symptom Questionnaire was completed by 74 patients with unilateral inserted indwelling stents. Additionally, six self-developed questions regarding type and quality of patient education on pain, urinary symptoms, hematuria, activities permitted, stent function and overall patient education were answered. Correlations between questionnaires, subscores and single items, and the influence on economic aspects were analyzed. RESULTS: Adjusting for age, sex, intravesical stent length, stent indwelling time, use of analgesics and an alpha-blocker, the correlation between the Ureteral Stent Symptom Questionnaire and self-developed questions was -0.40 (95% CI -0.58, -0.19, P < 0.001). The following subscores and items showed a statistically significant correlation with quality of patient education after correction for multiple testing: Ureteral Stent Symptom Questionnaire total score, urinary symptoms subscore, U6, U10, G3, G4 and GQ. No relevant influence of patient education on economic aspects was found. CONCLUSION: High-quality patient education on ureteral stent-related symptoms is highly advisable, as it has the potential to reduce these symptoms. However, the influence of information on the incidence and extent of potential problems seems to be limited. A much better approach would be to develop better designed devices and more convenient stent-free procedures.

Keywords: Ureteral Stent Symptom Questionnaire; morbidity; patient education; symptoms; ureteral catheterization
[25] D Abt, L Mordasini, E Warzinek, H-P Schmid, S R Haile, D S Engeler, and G Müllhaupt. Is intravesical stent position a predictor of associated morbidity? Korean Journal of Urology, 56(5):370 -- 378, May 2015. [ bib | DOI ]
Purpose: Temporary drainage of the upper urinary tract by use of internal ureteral stents is a common procedure that is often associated with a variety of symptoms. The role of intravesical stent position in associated morbidity is controversial. Materials and Methods: The German version of the ureteral stent symptom questionnaire (USSQ) was completed by 73 patients with an indwelling ureteral stent the day before stent removal. Intravesical stent position was classified into 3 categories by x-ray before stent removal. The influence of intravesical stent position on USSQ score was analyzed, including subscores and single items. Results: Intravesical stent position showed no significant influence on associated morbidity. The median USSQ total score in all patients was 77.5 (range, 30-147). Patients with ipsilateral stents (69.0; range, 30-122) tended to have lower total scores than did those with tangential (86.5; range, 30-122) or contralateral (77.0; range, 31-147) stents, but the differences were not statistically significant (p=0.35). The USSQ subscores for urinary symptoms (p=0.80), body pain (p=0.80), general health (p=0.16), work performance (p=0.07), additional problems (p=0.81), and all of the USSQ single items of interest in the context of stent length also did not differ significantly between the three groups. Conclusions: Intravesical stent position did not significantly influence associated morbidity in our study. An appropriate stent length should be chosen to avoid dislocation. However, complex calculations of optimum stent length, time-consuming manipulations, and costly stock holding of various stent sizes to obtain the perfect stent position do not seem worthwhile.

[26] M Greutmann, D Tobler, A Kovacs, M Greutmann-Yantiri, S R Haile, L Held, J Ivanov, W Williams, E Oechslin, C Silversides, and J Colman. Increasing mortality burden among adults with complex congenital heart disease. Congenital Heart Disease, 10(2):117--127, March/April 2015. [ bib | DOI ]
Background: Progress in management of congenital heart disease has shifted mortality largely to adulthood. However adult survivors with complex congenital heart disease are not cured and remain at risk of premature death as young adults. Thus, our aim was to describe the evolution and mortality risk of adult patient cohorts with complex congenital heart disease. Methods: Among 12,644 adults with congenital heart disease followed at a single center from 1980-2009, 176 had Eisenmenger syndrome, 76 had unrepaired cyanotic defects, 221 had atrial switch operations for transposition of the great arteries, 158 had congenitally corrected transposition of the great arteries, 227 had Fontan palliation, and 789 had repaired tetralogy of Fallot. We depict the 30 year evolution of these 6 patient cohorts, analyze survival probabilities in adulthood, and predict future number of deaths through 2029. Results: Since 1980 there has been a steady increase in numbers of patients followed except in cohorts with Eisenmenger syndrome and unrepaired cyanotic defects. Between 1980 and 2009, 308 patients in the study cohorts (19%) died. At the end of 2009, 85% of survivors were younger than 50 years. Survival estimates for all cohorts were markedly lower than for the general population, with important differences between cohorts. Over theupcoming two decades, we predict a substantial increase in numbers of deaths among young adults with subaortic right ventricles, Fontan palliation and repaired tetralogy of Fallot. Conclusions: Anticipatory action is needed to prepare clinical services for increasing numbers of young adults at risk of dying from complex congenital heart disease.

[27] S Niederer-Wüst, W Jochum, D Förbs, M Brändle, St Bilz, R Oettli, J Müller, SR Haile, S Ess, SJ Stoeckli, and MA Broglie. Impact of clinical risk scores and BRAF V600E mutation status on outcome in papillary thyroid cancer. Surgery, 157(1):119--125, January 2015. [ bib | DOI ]
Background: To evaluate the relationship between the BRAF V600E mutation and clinicopathologic parameters and to assess the impact of the BRAF V600E mutation and established risk scores on survival in patients with papillary thyroid carcinoma (PTC). Methods: Retrospective analysis of a consecutive, single-institutional cohort of patients with PTC larger than 1 cm. Clinical risk scores according to the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS), European Organisation for Research and Treatment of Cancer (EORTC), and tumor, node, metastases (TNM) scoring systems were determined. BRAF exon 15 mutation analysis was performed by polymerase chain reaction and Sanger sequencing. Results: BRAF V600E mutations were found in 75/116 (65%) PTC. The rates for 5- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 92% and 87%, 98% and 96%, and 96% and 94%, respectively. Low MACIS scores were associated with longer OS (10 y 95% vs 75%, P = .008), DSS (10 y 100% vs 89%, P = .02) and RFS (100% vs 85%, P = .006). Comparable survival advantages were observed for patients with early EORTC scores and low TNM stage. BRAF V600E mutation status was not associated with clinicopathologic characteristics of aggressive behavior such as extrathyroidal extension, lymph node metastases, higher T-categories, male sex, and greater age. Furthermore, BRAF V600E mutation status was not correlated with clinical risk scores and decreased survival. Conclusion: In concordance with other studies, we did not find a negative prognostic impact of a positive BRAF V600E mutation status on survival. In contrast, the risk algorithms MACIS, EORTC score, and TNM stage were associated with impaired prognosis. Therefore, clinical staging systems represent better tools for risk stratification than BRAF V600E mutation status.

[28] C Panje, T Panje, P M Putora, S-K Kim, S R Haile, D M Aebersold, and L Plasswilm. Guidance of treatment decisions in risk-adapted primary radiotherapy for prostate cancer using multiparametric magnetic resonance imaging: a single center experience. Radiation Oncology, 10(47), 2015. [ bib | DOI ]

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