Pablo E. Verde

Direct Genetic Analysis of Single Disseminated Cancer Cells for Prediction of Outcome and Therapy Selection in Esophageal Cancer

The increasing use of primary tumors as surrogate markers for prognosis and therapeutic decisions neglects evolutionary aspects of cancer progression. To address this problem, we studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers and prospectively analyzed single disseminated cancer cells from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients. Whole-genome screening revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. However, we identified chromosome 17q12-21, the region comprising HER2, as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death.

Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker

BackgroundTo evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies.MethodsThe Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up.ResultsEp-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor.ConclusionOur results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention.

Organisational downsizing and work stress: testing synergistic health effects in employed men and women

Study objective: To systematically study the separate and combined effects of organisational downsizing and work related stress on a measure of health in “survivors of layoffs”. Design: Using Rothman’s approach, separate and combined effects of the two exposures in estimating the risk of poor self rated health (work related symptoms) are analysed in a large sample of male and female employees. Setting: 0.1% cross sectional sample of the German working population. Participants: 12 240 men and 10 319 women, aged 16 to 59 years, surveyed in 1998–1999. Main results: Compared with the reference group, the group of participants who were simultaneously exposed to downsizing and work related stress (effort-reward imbalance) exhibited odds ratios (OR) of three or more work related symptoms that were by far higher (OR 4.41 in men and OR 5.37 in women) than those associated with single exposures. Altogether 21% (men) and 31% (women) of the effect size of the combined exposure was attributable to synergistic interaction. Conclusion: Although reduced health associated with organisational downsizing is partly attributable to an increase in work related stress these findings show an additional synergy effect produced by the combined exposure to both conditions.

Copy Number of Chromosome 17 but Not HER2 Amplification Predicts Clinical Outcome of Patients With Pancreatic Ductal Adenocarcinoma

PURPOSE To determine the frequency and the potential clinical use of HER2 (17q21) gene amplification and chromosome 17 aneuploidy in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS Serial tissue sections of 50 resected PDACs were analyzed with chromogenic in situ hybridization using locus-specific HER2 probes and centromeric probes for chromosome 17. Centromeric probes for chromosome 7 and 8 were hybridized to confirm ploidy levels. Expression of HER2 protein was assessed by immunohistochemistry. Correlations of experimental findings with clinical and follow-up data were tested. RESULTS The HER2 gene locus was frequently (24%) amplified in PDAC and the rate of overexpression (2+ and 3+) was 10%, but no prognostic significance was found. Copy number analysis of chromosomes 7, 8, and 17 revealed disomic (40%), trisomic (36%), and hypertetrasomic (24%) tumors. Compared with patients with disomic tumors, patients with hypertetrasomic tumors exhibited a significantly decreased relapse-free and overall survival (5.0 v 13.0 months, P = .0144 and 7.0 v 20.0 months, P = .0099, respectively). Multivariate analysis confirmed the independent prognostic significance of hypertetrasomy. CONCLUSION Tumor ploidy levels correlate with prognosis of PDAC patients, indicating characteristic biologic properties of PDAC with high chromosomal instability. In contrast, no prognostic influence on patient outcome was found for the amplification of the HER2 oncogene or p185(HER2) overexpression. Therefore, evaluation of ploidy levels offers new opportunities for patient stratification in clinical trials and enables novel approaches to study the well-known aggressiveness of PDAC.

Plasma micronutrient status is improved after a 3-month dietary intervention with 5 daily portions of fruits and vegetables: implications for optimal antioxidant levels

To explore the effects of increasing fruit and vegetable intake and the resulting effects on levels of circulating micronutrients in a community-dwelling population with an already high consumption of fruits and vegetables, 112 volunteers (86% women) underwent targeted dietary counseling for three months. At the beginning of the study and after 4, 8 and 12 weeks a food frequency questionnaire was filled in, and plasma levels of dietary antioxidants as well as biomarkers of oxidative lipid and protein damage were determined. Compared to baseline, especially the intake of fruits was significantly improved after 3 months of intervention, and mean plasma levels of lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene, retinol, α-tocopherol, vitamin C and vitamin B6 were increased. Biomarkers of oxidative stress remained unchanged. Thus, a nutritional counseling program is capable of improving plasma levels of antioxidants even in a health-conscious population. A decrease in biomarkers of oxidative stress, however, does not occur.

Left Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial

BACKGROUND Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia. METHODS A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007-2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly. RESULTS There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21. CONCLUSIONS Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

Neuropsychiatric and Cognitive Changes after Surgery for Primary Hyperparathyroidism

IntroductionNeuropsychiatric symptoms and cognitive impairment are mental manifestations of primary hyperparathyroidism (pHPT). The aim of our study was to determine if surgical treatment results in a long-lasting full recovery from these symptoms.MethodsIn a prospective case-control study with matching pairs, mental changes were examined preoperatively and 6 months postoperatively in 30 patients with primary hyperparathyroidism and 30 patients with nontoxic nodular goiter using the Hamilton depression score and four cognitive tests: DEM Tect, MWT (multiple word test), ZVT, and Benton test.ResultsPatients with pHPT demonstrated significantly more cognitive changes (P < 0.0001) with significant improvement 6 months postoperatively (P < 0.0001). Patients with pHPT presented more psychopathologic symptoms than patients of the control group (P = NS), and there was a tendency towards recovery in the pHPT group postoperatively. There was no correlation between biochemistry and psychopathologic or cognitive changes in the pHPT group.ConclusionsPatients with pHPT often present with neuropsychiatric symptoms and cognitive impairment. A successful parathyroid operation improves cognitive disorders in particular.

Two Short-Term Outcomes After Instituting a National Regulation Regarding Minimum Procedural Volumes for Total Knee Replacement

BACKGROUND Several studies have demonstrated positive relationships between high hospital volume and improved outcome following total knee replacement. To our knowledge, it has not been demonstrated whether improved outcomes are causally determined by selective referral to high-volume hospitals. We therefore evaluated the effect of a national regulation regarding minimum hospital volume for total knee replacement on two short-term outcome parameters. METHODS We performed a comparison of the years before (2004, 2005) and after (2006) the implementation of a national regulation on minimum hospital volume for total knee replacement through a secondary analysis of a national database on the quality of inpatient care in Germany as reflected by the number of cases per hospital and the postoperative rates of wound infection and wound hematoma or secondary hemorrhage. RESULTS We analyzed 110,349 cases from 2004, 118,922 cases from 2005, and 125,322 cases from 2006. Implementation of the regulation had a significant effect on the number of cases per hospital. Of the hospitals that had performed one to forty-nine cases in 2005, 35.6% moved to higher-volume categories and 21.2% dropped out in 2006. Multiple logistic regression analysis adjusting for patient characteristics demonstrated risk reductions of 22.5% (odds ratio, 0.775; 95% confidence interval, 0.700 to 0.857) for postoperative wound infection and of 44% (odds ratio, 0.562; 95% confidence interval, 0.531 to 0.596) for wound hematoma or secondary hemorrhage from 2005 to 2006. For wound infection, approximately half of the improvement was attributable to the effects of the minimum-volume regulation. For wound hematoma and secondary hemorrhage, the improvement could not be explained by the minimum-volume regulation. CONCLUSIONS Implementation of the minimum-volume regulation for total knee replacement resulted in more patients being managed at higher-volume hospitals than expected. Following the implementation of a minimum-volume regulation, effects on two short-term outcome parameters were observed, but definite conclusions could only be made regarding wound infection, with the minimum-volume regulation resulting in a decreased rate of infection.

Subclinical coronary atherosclerosis is more pronounced in men and women with lower socio-economic status: associations in a population-based study Coronary atherosclerosis and social status

Background Social inequalities of manifest coronary heart diseases are well documented in modern societies. Less evidence is available on subclinical atherosclerotic disease despite the opportunity to investigate processes underlying this association. Therefore, we examined the relationship between coronary artery calcification as a sign of subclinical coronary atherosclerosis, socio-economic status and established cardiovascular risk factors in a healthy population. Design Cross-sectional. Methods In a population-based sample of 4487 men and women coronary artery calcification was assessed by electron beam computed tomography quantified by the Agatston score. Socio-economic status was assessed by two indicators, education and income. First, we investigated associations between the social measures and calcification. Second, we assessed the influence of cardiovascular risk factors on this association. Results After adjustment for age, men with 10 and less years of formal education had a 70% increase in calcification score compared with men with high education. The respective increase for women was 80%. For income the association was weaker (among men 20% higher for the lowest compared with the highest quartile; and among women 50% higher, respectively). Consecutive adjustment for cardiovascular risk factors significantly attenuated the observed association of socio-economic status with calcification. Conclusions Social inequalities in coronary heart diseases seem to influence signs of subclinical coronary atherosclerosis as measured by coronary artery calcification. Importantly, cumulation of major cardiovascular risk factors in lower socio-economic groups accounted for a substantial part of this association.

Prevalence of Mild Cognitive Impairment and Its Subtypes in the Heinz Nixdorf Recall Study Cohort

Aims: We investigated the prevalence of mild cognitive impairment (MCI) and its subtypes according to the original (MCI-original) and modified (MCI-modified; neglecting cognitive complaints) Petersen criteria. Methods: 4,145 subjects (aged 50–80 years) from a German population-based study completed a cognitive screening test and were poststratified into 2 groups with sample sizes of 1,125 for impaired and 3,020 for age-appropriate performance. Random samples of 445 impaired participants and 211 age-appropriate participants received a detailed neuropsychological evaluation. The prevalence of MCI was estimated by a bias correction estimator based on stratum weights. The association between MCI and age, gender and education was analyzed in a logistic regression model. Results: The estimated MCI prevalence was 7.8% (95% CI: 5.7–9.9%) for the original, and 12.1% (95% CI: 9.8–14.4%) for the modified criteria. In the MCI-original group, amnestic MCI subtypes were slightly less common than non-amnestic MCI subtypes (3.5 vs. 4.3%). MCI-original was associated with lower education and older age. In the MCI-modified group, the amnestic subtypes were more common than the non-amnestic MCI subtypes (7.8 vs. 4.3%), and MCI was associated with age, gender and education. Conclusions: Prevalence rates of MCI are high in the general population and vary considerably according to the criteria applied.