Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer.

Keratins are the main identification markers of circulating tumor cells (CTCs); however, whether their deregulation is associated with the metastatic process is largely unknown. Previously we have shown by in silico analysis that keratin 16 (KRT16) mRNA upregulation might be associated with more aggressive cancer. Therefore, in this study, we investigated the biological role and the clinical relevance of K16 in metastatic breast cancer. By performing RT-qPCR, western blot, and immunocytochemistry, we investigated the expression patterns of K16 in metastatic breast cancer cell lines and evaluated the clinical relevance of K16 expression in CTCs of 20 metastatic breast cancer patients. High K16 protein expression was associated with an intermediate mesenchymal phenotype. Functional studies showed that K16 has a regulatory effect on EMT and overexpression of K16 significantly enhanced cell motility (p < 0.001). In metastatic breast cancer patients, 64.7% of the detected CTCs expressed K16, which was associated with shorter relapse-free survival (p = 0.0042). Our findings imply that K16 is a metastasis-associated protein that promotes EMT and acts as a positive regulator of cellular motility. Furthermore, determining K16 status in CTCs provides prognostic information that helps to identify patients whose tumors are more prone to metastasize

Clonality of circulating tumor cells in breast cancer brain metastasis patients

BACKGROUND: The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. METHODS: Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). RESULTS: CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. CONCLUSION: The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure

Five to seven percent of lung tumours are estimated to occur because of occupational asbestos exposure. Using cDNA microarrays, we have earlier detected asbestos exposure-related genomic regions in lung cancer. The region at 2p was one of those that differed most between asbestos-exposed and non-exposed patients. Now, we evaluated genomic alterations at 2p22.1-p16.1 as a possible marker for asbestos exposure. Lung tumours from 205 patients with pulmonary asbestos fibre counts from 0 to 570 million fibres per gram of dry lung, were studied by fluorescence in situ hybridisation (FISH) for DNA copy number alterations (CNA). The prevalence of loss at 2p16, shown by three different FISH probes, was significantly increased in lung tumours of asbestos-exposed patients compared with non-exposed (P=0.05). In addition, a low copy number loss at 2p16 associated significantly with high-level asbestos exposure (P=0.02). Furthermore, 27 of the tumours were studied for allelic imbalances (AI) at 2p22.1–p16.1 using 14 microsatellite markers and also AI at 2p16 was related to asbestos exposure (P=0.003). Our results suggest that alterations at 2p16 combined with other markers could be useful in diagnosing asbestos-related lung cancer

Prevalence, New Incidence, Course, and Risk Factors of PTSD, Depression, Anxiety, and Panic Disorder during the Covid-19 Pandemic in 11 Countries

We aimed to evaluate the prevalence and incidence of post-traumatic stress disorder (PTSD), depression, anxiety, and panic disorder (PD) among citizens in 11 countries during the Covid-19 pandemic. We explored risks and protective factors most associated with the development of these mental health disorders and their course at 68 days follow up. We acquired 9543 unique responses via an online survey that was disseminated in UK, Belgium, Netherlands, Bulgaria, Czech Republic, Finland, India, Latvia, Poland, Romania, and Sweden. The prevalence and new incidence during the pandemic for at least one disorder was 48.6% and 17.6%, with the new incidence of PTSD, anxiety, depression, and panic disorder being 11.4%, 8.4%, 9.3%, and 3%, respectively. Higher resilience was associated with lower mental health burden for all disorders. Ten to thirteen associated factors explained 79% of the variance in PTSD, 80% in anxiety, 78% in depression, and 89% in PD. To reduce the mental health burden, governments should refrain from implementing many highly restrictive and lasting containment measures. Public health campaigns should focus their effort on alleviating stress and fear, promoting resilience, building public trust in government and medical care, and persuading the population of the measures' effectiveness. Psychosocial services and resources should be allocated to facilitate individual and community-level recovery from the pandemic

EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer

Introduction: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. Methods: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. Results: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p &lt; 0·001; ≥5 CTCs: HR = 2.21, p &lt; 0·001) and overall survival (≥2 CTCs: HR = 2·18, p &lt; 0·001; ≥5 CTCs: HR = 2·75, p &lt; 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p &lt; 0·001; ≥2 CTCs p &lt; 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. Conclusions: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models

EPAC-Lung:Pooled analysis of circulating tumor cells in advanced non-small cell lung cancer

Background: We assessed the clinical validity of circulating tumor cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a European pooled analysis of individual patient data. This is the largest study of its kind and the first to examine between-centre heterogeneity of CTC identification in NSCLC.Methods: Nine European NSCLC CTC centers were asked to provide reported/unreported anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 - March 2017. We used Cox regression models, stratified by centre, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinico-pathological models using likelihood ratio (LR) statistics and c-indices.Results: Seven out of nine eligible centers provided data for 550 eligible patients, including 209 patients whose prognostic information was previously unpublished. CTC counts of ≥ 2 and ≥5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: HR 1.72, p &lt; 0·001; ≥5 CTCs: HR 2.21, p &lt; 0·001) and overall survival (≥2 CTCs: HR 2·18, p &lt; 0·001; ≥5 CTCs: HR 2·75, p &lt; 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinico-pathological models (log-transformed CTCs p &lt; 0·0001; ≥2 CTCs p &lt; 0·0001; ≥5 CTCs p &lt; 0·0001), while more moderate improvements were observed with the use of c-index models. There was minor evidence of between-center heterogeneity in the effect on PFS, but not OS.No difference in CTC profile was observed between key NSCLC molecular subsets such as EGFR, ALK, and KRAS.Conclusions: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC. CTC count improves prognostication when added to full clinico-pathological predictive models. ≥2 CTCs is an appropriate cutoff to move towards establishing clinical utility