Eik Vettorazzi

Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy.

In a large population‐based case–control study in Germany, including 3,464 breast cancer cases aged 50–74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face‐to‐face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%‐confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55–1.94) and heterogeneous by histological type (p < 0.01), being more than 2‐fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04–1.06) for continuous combined estrogen–progestagen, 1.03 (95% CI, 1.02–1.04) for cyclical EP and 1.01 (95% CI, 1.00–1.03) for estrogen‐only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone‐ or levonorgestrel‐derived progestagens than for continuously administered progesterone‐derived progestagens (OR, 2.27, 95% CI, 1.98–2.62 vs. 1.47, 95% CI, 1.12–1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose.

Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial:

Background: Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. Objective: To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. Methods: Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4–6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8–10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. Results: A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. Conclusion: This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. Trial Registration: ISRCTN (trial number 76467492) http://isrctn.org

Vitamin D Deficiency Induces Early Signs of Aging in Human Bone, Increasing the Risk of Fracture

In addition to decreasing bone mass, vitamin D deficiency causes early aging of the remaining mineralized bone and leads to severe losses in fracture resistance. Vitamin D–Deficient Bone Showing Its Age Vitamin D, which is sometimes called the “sunshine vitamin” because humans can synthesize it in the presence of sunlight, has long been associated with prevention of bone disease. Vitamin D is required for proper absorption of calcium and its uptake into bone, and a lack of vitamin D is known to cause rickets and osteomalacia—diseases in which bone is too soft because of excessive collagenous matrix and its inadequate mineralization. Now, Busse and co-authors provide some evidence that the reverse is also partially true, and vitamin D deficiency can result in areas of overly dense mineralization in the bone. To study the effects of vitamin D deficiency, Busse and colleagues used samples of bone from 30 apparently healthy people. Half of these subjects were deficient in vitamin D, defined by low concentration of vitamin D in the blood and altered macroscopic characteristics of the bone. Through detailed analysis of bone structure and functional tests measuring the bones’ resistance to cracking, the authors characterized the ways in which vitamin D–deficient bone differs from normal. As expected, they found that bones from vitamin D–deficient subjects had a much thicker layer of unmineralized osteoid coating the surface of mineralized bone. However, they also demonstrated that the bone underneath this osteoid layer was more heavily mineralized than normal and had structural characteristics of older and more brittle bone. They explained this phenomenon by noting that osteoclasts, cells that normally remodel the bone, cannot get through the thick osteoid layer. As a result, the areas of bone hidden underneath the osteoid continue to age and mineralize even as the overall bone mineral content progressively decreases. These interesting and unexpected findings about human bone emphasize the negative consequences of vitamin D deficiency, which is all too common, especially at northern latitudes. Additional work will be needed to translate this knowledge into clinical practice, but the detailed understanding of human bone structure may provide some insight into more effective ways to prevent or treat fractures in patients with vitamin D deficiency. Vitamin D deficiency is a widespread medical condition that plays a major role in human bone health. Fracture susceptibility in the context of low vitamin D has been primarily associated with defective mineralization of collagenous matrix (osteoid). However, bone’s fracture resistance is due to toughening mechanisms at various hierarchical levels ranging from the nano- to the microstructure. Thus, we hypothesize that the increase in fracture risk with vitamin D deficiency may be triggered by numerous pathological changes and may not solely derive from the absence of mineralized bone. We found that the characteristic increase in osteoid-covered surfaces in vitamin D–deficient bone hampers remodeling of the remaining mineralized bone tissue. Using spatially resolved synchrotron bone mineral density distribution analyses and spectroscopic techniques, we observed that the bone tissue within the osteoid frame has a higher mineral content with mature collagen and mineral constituents, which are characteristic of aged tissue. In situ fracture mechanics measurements and synchrotron radiation micro–computed tomography of the crack path indicated that vitamin D deficiency increases both the initiation and propagation of cracks by 22 to 31%. Thus, vitamin D deficiency is not simply associated with diminished bone mass. Our analyses reveal the aged nature of the remaining mineralized bone and its greatly decreased fracture resistance. Through a combination of characterization techniques spanning multiple size scales, our study expands the current clinical understanding of the pathophysiology of vitamin D deficiency and helps explain why well-balanced vitamin D levels are essential to maintain bone’s structural integrity.

Hepatitis E Seroprevalence in Europe: A Meta-Analysis

There have been large numbers of studies on anti-HEV IgG seroprevalence in Europe, however, the results of these studies have produced high variability of seroprevalence rates, making interpretation increasingly problematic. Therefore, the aim of this study was to develop a clearer understanding of anti-HEV IgG seroprevalence in Europe and identify risk groups for HEV exposure by a meta-analysis of published studies. Methods: All European HEV-seroprevalence studies from 2003 to 2015 were reviewed. Data were stratified by assay, geographical location, and patient cohort (general population, patients with HIV, solid-organ transplant recipients, chronic liver disease patients, and individuals in contact with swine/wild animals). Data were pooled using a mixed-effects model. Results: Four hundred thirty-two studies were initially identified, of which 73 studies were included in the analysis. Seroprevalence estimates ranged from 0.6% to 52.5%, increased with age, but were unrelated to gender. General population seroprevalence varied depending on assays: Wantai (WT): 17%, Mikrogen (MG): 10%, MP-diagnostics (MP): 7%, DiaPro: 4%, Abbott 2%. The WT assay reported significantly higher seroprevalence rates across all cohorts (p < 0.001). Individuals in contact with swine/wild animals had significantly higher seroprevalence rates than the general population, irrespective of assay (p < 0.0001). There was no difference between any other cohorts. The highest seroprevalence was observed in France (WT: 32%, MP: 16%) the lowest in Italy (WT: 7.5%, MP 0.9%). Seroprevalence varied between and within countries. The observed heterogeneity was attributed to geographical region (23%), assay employed (23%) and study cohort (7%). Conclusion: Seroprevalcence rates primarily depend on the seroassy that is used, followed by the geographical region and study cohort. Seroprevalence is higher in individuals exposed to swine and/or wild animals, and increases with age.

Shock efficacy of subcutaneous implantable cardioverter-defibrillator for prevention of sudden cardiac death: initial multicenter experience.

Background—Recently, subcutaneous implantable cardioverter-defibrillator (S-ICD) has become available. The aim of our study was to assess the efficacy of S-ICD in a clinical setting. Methods and Results—Between June 2010 and July 2011, 40 consecutive patients (42±15 years; body mass index, 27±6 kg/m2; left ventricular ejection fraction, 47±15%; 28 men) received an S-ICD for primary (n=17) or secondary prevention (n=23 [58%]) at 3 institutions in Germany. Intraoperative defibrillation efficacy testing failed in 1 patient with severely reduced left ventricular ejection fraction; testing was effective in all other patients. All episodes stored in the S-ICD were analyzed for appropriate and inappropriate detection, as well as effective shock delivery to convert ventricular tachyarrhythmia into sinus rhythm. During a median follow-up of 229 (interquartile range, 116–305) days, 4 patients experienced 21 episodes, with correct detection of ventricular tachyarrhythmia and subsequent shock therapy. A total of 28 shocks were delivered in these 4 patients. Mixed logistic regression modeling revealed a shock efficacy of 96.4% (95% CI, 12.8%–100%). The efficacy of first shocks, however, was only 57.9% (95% CI, 35.6%–77.4%). Four episodes were incorrectly classified as ventricular tachyarrhythmia, which led to inappropriate shock delivery in 2 patients. Conclusions—Ineffective shock delivery may occur in patients with S-ICD, even after successful intraoperative testing. Multicenter trials are required with close monitoring of safety and efficacy end points to identify patients who may be at risk for shock failure.

Occludin Is Involved in Adhesion, Apoptosis, Differentiation and Ca2+-Homeostasis of Human Keratinocytes: Implications for Tumorigenesis

Tight junction (TJ) proteins are involved in a number of cellular functions, including paracellular barrier formation, cell polarization, differentiation, and proliferation. Altered expression of TJ proteins was reported in various epithelial tumors. Here, we used tissue samples of human cutaneous squamous cell carcinoma (SCC), its precursor tumors, as well as sun-exposed and non-sun-exposed skin as a model system to investigate TJ protein alteration at various stages of tumorigenesis. We identified that a broader localization of zonula occludens protein (ZO)-1 and claudin-4 (Cldn-4) as well as downregulation of Cldn-1 in deeper epidermal layers is a frequent event in all the tumor entities as well as in sun-exposed skin, suggesting that these changes result from chronic UV irradiation. In contrast, SCC could be distinguished from the precursor tumors and sun-exposed skin by a frequent complete loss of occludin (Ocln). To elucidate the impact of down-regulation of Ocln, we performed Ocln siRNA experiments in human keratinocytes and uncovered that Ocln downregulation results in decreased epithelial cell-cell adhesion and reduced susceptibility to apoptosis induction by UVB or TNF-related apoptosis-inducing ligand (TRAIL), cellular characteristics for tumorigenesis. Furthermore, an influence on epidermal differentiation was observed, while there was no change of E-cadherin and vimentin, markers for epithelial-mesenchymal transition. Ocln knock-down altered Ca2+-homeostasis which may contribute to alterations of cell-cell adhesion and differentiation. As downregulation of Ocln is also seen in SCC derived from other tissues, as well as in other carcinomas, we suggest this as a common principle in tumor pathogenesis, which may be used as a target for therapeutic intervention.

Age- and sex-related changes of humeral head microarchitecture: Histomorphometric analysis of 60 human specimens†

Fractures of the humeral head are frequent and will further increase due to demographic changes. Prior to operative fracture treatment, the regional differences of bone quality, especially of elderly people, have to be carefully considered to assure stable implant fixation. However, conclusive data concerning the variation of histomorphometric parameters are still lacking. Consequently, the purpose of this study was to analyze the age‐ and sex‐related changes in bone microarchitecture. For that reason, 60 proximal humeri were harvested from patients at autopsy. Twelve regions of interest (ROI) were defined for each centered coronar humeral head slice and the specimens were subjected to radiographic, histological, and histomorphometric analyses. We could demonstrate that in contrast to men, women over 60 years of age had a significant age‐related decrease in bone mass. The most prominent decrease was observed in the region of the greater tuberosity, which represents an osteoporotic fracture site. The most superior and medially located part of the centered coronar humeral head slice showed, independent from age and sex, the highest bone mass and can therefore be considered as the best location for subchondral screw placement. Taken together, our study revealed distinct sex‐related changes of the humeral head bone microarchitecture with aging, which should be considered in implant positioning.

Actual and Predicted Survival Time of Patients With Spinal Metastases of Lung Cancer : Evaluation of the Robustness of the Tokuhashi Score

Study Design. In a retrospective analysis we evaluated the achieved and the predicted survival times according to the Tokuhashi score for patients with spinal metastases of lung cancer (lc). Objective. Our aim was to investigate the robustness of the Tokuhashi Score for this group of patients. Summary of Background Data. The decision on operative versus conservative treatment for cancer patients with vertebral metastases depend on their predicted lifespan. Although the score of Tokuhashi is commonly used for prognostic predictions, its reliability for specific tumor types (e.g., lc), has not been validated. Methods. Seventy-six patients who had undergone spinal surgery for lc metastases between 1999 and 2004 were verified according to the Tokuhashi score and predicted versus achieved survival times were compared. Results. The median overall survival (OS) after surgery for all patients was 108 (3–1767) days (102 [5–1767] days for patients with NSCLC [n = 49; 64.5%] and 108 [3–473] days for patients with SCLC [n = 24; 31.6%]). Survival times differed depending on the time period of procedure performance (OS 81 [3–435] days for patients operated between 1999 and 2001 [n = 38], 135 [8–1767] days for patients who received surgery between 2002 and 2004 [n = 38]). Actual and predicted survival were similar in 51 of 76 cases (67.1%), while there was no correlation in 25 of 76 (32.9%) cases. Results were comparable for all histologic subgroups. Conclusion. Although the survival time of patients with vertebral metastases from lc has increased over the last 10 years, the overall outcome is still poor. For the prediction of an individual prognosis in the group of lc patients the score of Tokuhashi seems to be a suboptimal tool. We conclude that therapeutic decisions for such patients should be made based on interdisciplinary platforms, especially in the light of improved systemic treatment options.

Effects of a Psychological Internet Intervention in the Treatment of Mild to Moderate Depressive Symptoms: Results of the EVIDENT Study, a Randomized Controlled Trial

Background: Mild to moderate depressive symptoms are common but often remain unrecognized and treated inadequately. We hypothesized that an Internet intervention in addition to usual care is superior to care as usual alone (CAU) in the treatment of mild to moderate depressive symptoms in adults. Methods: This trial was controlled, randomized and assessor-blinded. Participants with mild to moderate depressive symptoms (Patient Health Questionnaire, PHQ-9, score 5-14) were recruited from clinical and non-clinical settings and randomized to either CAU or a 12-week Internet intervention (Deprexis) adjunctive to usual care. Outcomes were assessed at baseline, 3 months (post-assessment) and 6 months (follow-up). The primary outcome measure was self-rated depression severity (PHQ-9). The main analysis was based on the intention-to-treat principle and used linear mixed models. Results: A total of 1,013 participants were randomized. Changes in PHQ-9 from baseline differed significantly between groups (t825 = 6.12, p < 0.001 for the main effect of group). The post-assessment between-group effect size in favour of the intervention was d = 0.39 (95% CI: 0.13-0.64). It was stable at follow-up, with d = 0.32 (95% CI: 0.06-0.69). The rate of participants experiencing at least minimally clinically important PHQ-9 change at the post-assessment was higher in the intervention group (35.6 vs. 20.2%) with a number needed to treat of 7 (95% CI: 5-10). Conclusions: The Internet intervention examined in this trial was superior to CAU alone in reducing mild to moderate depressive symptoms. The magnitude of the effect is clinically important and has public health implications.

Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation

BACKGROUND Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. METHODS Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. RESULTS Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Grays test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Grays test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). CONCLUSIONS Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.