Roland Seiler

Trained men show lower cortisol, heart rate and psychological responses to psychosocial stress compared with untrained men

Physical activity has proven benefits for physical and psychological well-being and is associated with reduced responsiveness to physical stress. However, it is not clear to what extent physical activity also modulates the responsiveness to psychosocial stress. The purpose of this study was to evaluate whether the reduced responsiveness to physical stressors that has been observed in trained men can be generalized to the modulation of physiological and psychological responses to a psychosocial stressor. Twenty-two trained men (elite sportsmen) and 22 healthy untrained men were exposed to a standardized psychosocial laboratory stressor (Trier Social Stress Test). Adrenocortical (salivary free cortisol levels), autonomic (heart rate), and psychological responses (mood, calmness, anxiety) were repeatedly measured before and after stress exposure. In response to the stressor, cortisol levels and heart rate were significantly increased in both groups, without any baseline differences between groups. However, trained men exhibited significantly lower cortisol and heart rate responses to the stressor compared with untrained men. In addition, trained men showed significantly higher calmness and better mood, and a trend toward lower state anxiety during the stress protocol. On the whole, elite sportsmen showed reduced reactivity to the psychosocial stressor, characterized by lower adrenocortical, autonomic, and psychological stress responses. These results suggest that physical activity may provide a protective effect against stress-related disorders.

The level of physical activity affects adrenal and cardiovascular reactivity to psychosocial stress

Physical activity plays a key role in the control of neuroendocrine, autonomic, and behavioral responses to physical and psychosocial stress. However, little is known about how the level of physical activity modulates stress responsiveness. Here, we test whether different levels of physical activity are associated with different adrenal, cardiovascular, and psychological responses to psychosocial stress. In addition, competitiveness is assessed as a personality trait that possibly modulates the relationship between physical activity and stress reactivity. Eighteen elite sportsmen, 50 amateur sportsmen, and 24 untrained men were exposed to a standardized psychosocial laboratory stressor (Trier Social Stress Test). Repeated measures of salivary free cortisol, heart rate, and psychological responses to psychosocial stress were compared among the 3 study groups. Elite sportsmen exhibited significantly lower cortisol, heart rate, and state anxiety responses compared with untrained subjects. Amateur sportsmen showed a dissociation between sympathetic and hypothalamic-pituitary-adrenal responsiveness to stress, with significantly reduced heart rate responses but no difference in cortisol responses compared with untrained men. Different levels of competitiveness among groups did not mediate stress reactivity. Our results are in line with previous studies indicating reduced reactivity of the autonomic nervous system to psychosocial stress in trained individuals. More importantly, these findings imply a differential effect of the level of physical activity on different stress-related neurophysiological systems in response to psychosocial stress.

Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy

BACKGROUND An early report on the molecular subtyping of muscle-invasive bladder cancer (MIBC) by gene expression suggested that response to neoadjuvant chemotherapy (NAC) varies by subtype. OBJECTIVE To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. DESIGN, SETTING, AND PARTICIPANTS Whole transcriptome profiling was performed on pre-NAC transurethral resection specimens from 343 patients with MIBC. Samples were classified according to four published molecular subtyping methods. We developed a single-sample genomic subtyping classifier (GSC) to predict consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal) with highest clinical impact in the context of NAC. Overall survival (OS) according to subtype was analyzed and compared with OS in 476 non-NAC cases (published datasets). INTERVENTION Gene expression analysis was used to assign subtypes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Receiver-operating characteristics were used to determine the accuracy of GSC. The effect of GSC on survival was estimated by Cox proportional hazard regression models. RESULTS AND LIMITATIONS The models generated subtype calls in expected ratios with high concordance across subtyping methods. GSC was able to predict four consensus molecular subtypes with high accuracy (73%), and clinical significance of the predicted consensus subtypes could be validated in independent NAC and non-NAC datasets. Luminal tumors had the best OS with and without NAC. Claudin-low tumors were associated with poor OS irrespective of treatment regimen. Basal tumors showed the most improvement in OS with NAC compared with surgery alone. The main limitations of our study are its retrospective design and comparison across datasets. CONCLUSIONS Molecular subtyping may have an impact on patient benefit to NAC. If validated in additional studies, our results suggest that patients with basal tumors should be prioritized for NAC. We discovered the first single-sample classifier to subtype MIBC, which may be suitable for integration into routine clinical practice. PATIENT SUMMARY Different molecular subtypes can be identified in muscle-invasive bladder cancer. Although cisplatin-based neoadjuvant chemotherapy improves patient outcomes, we identified that the benefit is highest in patients with basal tumors. Our newly discovered classifier can identify these molecular subtypes in a single patient and could be integrated into routine clinical practice after further validation.

Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours.

BACKGROUND Her2, an alias for the protein of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), might be an attractive therapeutic target in metastasising bladder cancer. Genotype and phenotype of primary tumours and their metastases may differ. OBJECTIVES Determine Her2 status in both tumour components to better assess the potential of anti-Her2 therapies. DESIGN, SETTING, AND PARTICIPANTS Histologic examination revealed lymph node metastases in 150 patients with urothelial bladder cancer clinically staged as N0M0. A tissue microarray was constructed with four tumour samples per patient: two from the primary tumour and two from nodal metastases. Her2 status was determined at the gene level by fluorescence in situ hybridisation (FISH) and at the protein level by immunohistochemistry (IHC). INTERVENTIONS All patients underwent cystectomy and standardised extended lymphadenectomy. MEASUREMENTS Overall survival was assessed according to HER2 gene status and protein expression in primary bladder cancers and lymph node metastases. RESULTS AND LIMITATIONS Her2 amplification was significantly more frequent in lymph node metastases (15.3%) than in matched primary bladder cancers (8.7%; p = 0.003). Her2 amplification in primary tumours was highly preserved in the corresponding metastases as indicated by only one amplified primary tumour without amplification of the metastasis. There was a high concordance in HER2 FISH results between both samples from the primary tumour (κ = 0.853) and from the metastases (κ = 0.930). IHC results were less concordant (κ=0.539 and 0.830). FISH and IHC results were poorly correlated in primary tumours (κ = 0.566) and metastases (κ = 0.673). While Her2 amplification in the primary tumour significantly predicted poor outcome (p = 0.044), IHC-based survival prediction was unsuccessful. CONCLUSIONS Her2 amplification in metastasising bladder cancer is relatively frequent, is homogeneous in each tumour component, and predicts early death. This suggests a high potential for anti-Her2 therapies. For patient selection, FISH might be more accurate than IHC.

Effects of a lifestyle physical activity intervention on stages of change and energy expenditure in sedentary employees.

Abstract Objectives: To assess the effects of an intervention in a worksite setting on changes in physical activity. It was expected that an intervention with an emphasis on daily life activities, such as brisk walking, would increase the proportion of individuals expending more than 1000 kcal per week in activities with at least moderate intensity, or influence individuals to change from one stage of the Transtheoretical Model of Behaviour to a higher one. Design: Quasi-experimental. Data were collected before and after a 4 month intervention period in 6 offices ( n =211) of the Swiss federal administration. Two offices ( n =168) served as controls. Methods: Participants completed a 7 day recall questionnaire on physical activities (daily life activities, leisure time activities, and sport) and stages of readiness for change, along with questions on demographic variables. Components of the intervention programme were: information, actions for daily life activities, fitness lessons, and counselling. Results: Between precontemplation/contemplation, preparation, and action/maintenance there was a significant difference of more than 850 kcal of energy expenditure. Baseline and follow-up examinations revealed a significant progression across the stages of change in the intervention offices. Subgroup analyses showed that the level of physical activity at baseline influenced the effect of the intervention. Exclusively in worksites with a lower proportion of sufficiently active individuals, the intervention was able to substantially increase the proportion by 21%. Conclusions: A diversified intervention programme in a worksite setting encourages participants to become more physically active during work and leisure time.

CCND1 /CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60–70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5–20% immunostained tumor nuclei; P<0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P=0.001) and metastases (P=0.02) and high nuclear CyclinD1 in metastases (P=0.01) predicted early cancer-related death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.

Taiji practice attenuates psychobiological stress reactivity — A randomized controlled trial in healthy subjects

BACKGROUND Stress reducing effects of Taiji, a mindful and gentle form of body movement, have been reported in previous studies, but standardized and controlled experimental studies are scarce. The present study investigates the effect of regular Taiji practice on psychobiological stress response in healthy men and women. METHODS 70 participants were randomly assigned to either Taiji classes or a waiting list. After 3 months, 26 (8 men, 18 women) persons in the Taiji group and 23 (9 men, 14 women) in the waiting control group underwent a standardized psychosocial stress test combining public speaking and mental arithmetic in front of an audience. Salivary cortisol and α-amylase, heart rate, and psychological responses to psychosocial stress were compared between the study groups. (ClinicalTrials.gov number, NCT01122706.) RESULTS Stress induced characteristic changes in all psychological and physiological measures. Compared to controls, Taiji participants exhibited a significantly lower stress reactivity of cortisol (p = .028) and heart rate (p = .028), as well as lower α-amylase levels (p = .049). They reported a lower increase in perceived stressfulness (p = .006) and maintained a higher level of calmness (p = .019) in response to psychosocial stress. CONCLUSION Our results consistently suggest that practicing Taiji attenuates psychobiological stress reactivity in healthy subjects. This may underline the role of Taiji as a useful mind-body practice for stress prevention.

Androgen receptors are differentially expressed in Gleason patterns of prostate cancer and down-regulated in matched lymph node metastases

Androgen receptor (AR) expression profile in the different Gleason patterns (GP) of primary prostate cancers and nodal metastases is unknown. More information about AR distribution is needed to optimize evaluation methods and to better understand the role of AR in development and progression of prostate cancer.

Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, is Effective in HER2 Over Expressing Bladder Cancer

PURPOSE Systemic therapy for advanced bladder cancer has not changed substantially in more than 2 decades and mortality rates remain high. The recognition of HER2 over expression in bladder cancer has made HER2 a promising therapeutic target. T-DM1, a new drug consisting of the HER2 antibody trastuzumab conjugated with a cytotoxic agent, has been shown in breast cancer to be superior to trastuzumab. We tested T-DM1 in preclinical models of bladder cancer. MATERIALS AND METHODS We evaluated the effect of T-DM1 compared to trastuzumab in different in vitro and in vivo models of HER2 over expressing bladder cancer. RESULTS RT4V6 was the highest HER2 expressing bladder cancer cell line and it showed higher growth inhibition with T-DM1 compared to trastuzumab. T-DM1 but not trastuzumab induced apoptosis of RT4V6 cells after G2/M arrest on cell cycle analysis. HER2 expression was higher in cell lines with acquired cisplatin resistance compared to the corresponding parental cell lines. Resistant cells showed higher sensitivity to T-DM1 by the induction of apoptosis. In addition, cells cultured in anchorage independent conditions increased HER2 expression compared to cells cultured in adherent conditions and T-DM1 significantly inhibited colony formation in soft agar compared to trastuzumab. In an orthotopic bladder cancer xenograft model tumor growth of cisplatin resistant RT112 was significantly inhibited by T-DM1 via the induction of apoptosis compared to treatment with control IgG or trastuzumab. CONCLUSIONS T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer.

Pelvic lymph nodes: distribution and nodal tumour burden of urothelial bladder cancer

Aims To evaluate the number of lymph nodes and the lymph node tumour burden in different anatomical pelvic regions to better asses the impact of variations in the extent of lymphadenectomy on reported LN parameters and pelvic tumour clearance. Methods 162 patients with lymph-node-positive urothelial carcinoma of the bladder were treated by cystectomy and extended pelvic lymphadenectomy. Various lymph node parameters were determined separately for the three pelvic regions (external iliac, obturator and internal iliac). Results Of 4080 evaluated lymph nodes (median 25 per patient, range 8–55) 39%, 35% and 26% (p<0.05) were found in the external iliac, obturator and internal iliac region, respectively. The distribution of the 625 lymph node metastases (median two per patient, range 1–35) was not significantly different between the regions (external iliac 33%, obturator 38%, internal iliac 29%). However, the median diameter of largest metastasis and total diameter of all metastases were smallest in the internal iliac region (external iliac 0.85 cm, 1.1 cm; obturator 0.8 cm, 1.0 cm; internal iliac 0.6 cm, 0.8 cm; p<0.03, p<0.05; for median diameter of largest metastasis and total diameter of all metastases, respectively). Metastases in only one region were found in 33% of patients (external iliac 13%, obturator 10%, internal iliac 10%); these three groups showed no significant difference in survival. No difference was detected in lymph node parameters between genders. Conclusions Lymph node counts and retrieval of metastases depends on the extent of pelvic lymphadenectomy. Dissection not including the internal iliac region misses 26% of all pelvic lymph nodes, 29% of metastases, and understages a substantial number of patients as pN0 (10%).