Veronika Weyer

Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme

Aim To identify a means to objectively measure corneal clouding in patients with mucopolysaccharidosis in a prospective controlled clinical trial. Methods Corneal haze was assessed by slit lamp examination and measured using the densitometry programme of the Pentacam, a rotating Scheimpflug camera in 33 mucopolysaccharidoses (MPS) patients and 32 controls. Results Pentacam measurements were available in 31 right and 31 left eyes of 32 patients and in 32 left and right eyes of 32 subjects in the control group. Slit lamp findings correlated very well with corneal density measurements (Spearman correlation right eye (OD)/left eye (OS)=0.782/0.791). MPS patients had higher density units (median OD/OS=14.1/14.7) than control subjects (median OD/OS=6.7/6.9, p<0.001). In patients, the corneal centre density values (median OD/OS=13.8/14.0) did not differ from corneal periphery values (median OD/OS=14.3/14.7). Conclusions The densitometry programme of the Pentacam provides objective measurement of corneal haze in mucopolysaccharidosis patients.

Depression, Anxiety and Quality of Life in Long-Term Survivors of Malignant Melanoma: A Register-Based Cohort Study

Aim The purpose of the study was to determine anxiety and depression, quality of life, and their determinants in long-term survivors of malignant melanoma. Methods In a state cancer registry a cohort of survivors of malignant melanoma was contacted via the physician registered. Of 1302 contactable patients, 689 (52.2%) completed a questionnaire including the Patient Health Questionnaire with generalized anxiety (GAD-7) and depression (PHQ-9) and the EORTC Quality of Life Questionnaire (EORTC QLQ 30). Based on multiple regression analysis, predictors of quality of life and distress were identified. Comparison data were assessed in two waves of representative face-to-face household surveys of the adult German population. Results An average of 8.4 (5.7 to 12.2) years after diagnosis, distress was higher in women compared to men and in middle adulthood (vs. older patients). Symptoms were higher in women than in men, and there was a decline of functioning and increase of symptoms across the age range of both genders. Compared to the general population, there were slightly increased depression and anxiety (only women), but no impaired global quality of life. Yet, survivors evidenced functional decline and more physical symptoms. Distress and reduced quality of life were consistently predicted by lack of social support, fear of recurrence, pessimism and self-blame. Distress was increased by a family history of melanoma, and additional mental and somatic diseases. Conclusion Overall, long-term survivors have adjusted well achieving a global quality of life comparable to the general population. Yet, compromised functional dimensions, physical symptoms and distress indicate the need for integrating psychooncological screening into oncological follow-up, which might be guided by predictors such as family history or social support. Further prospective study is needed to determine the course of adaptation to the disease and corroborate the risk factors identified.

Influence of a bioceramic root end material and mineral trioxide aggregates on fibroblasts and osteoblasts.

OBJECTIVE The biocompatibility of materials used in endodontic treatment is of high importance, because they can come in contact with periradicular tissues and there is a risk of possible systemic toxicity. The aim of the present study was to investigate the in vitro reaction to a bioceramic based root end material in comparison to mineral trioxide aggregates (MTA) as the established gold standard. DESIGN The root end materials grey MTA Angelus (GMTA), white MTA Angelus (WMTA), ProRoot MTA, and EndoSequence Root Repair Material (ERRM) were incubated with human periodontal ligament fibroblasts and osteoblasts (10(4)cells/ml) for up to 96h. Cell proliferation (RFU) was determined by means of the Alamar Blue assay. In addition, fluorescence staining was carried out to visually monitor cell growth and morphology. RESULTS For most of the observational time period of up to 96h, there was no statistically significant difference between the proliferation rates of the control cells and those in contact with ERRM. In contrast, the mineral trioxide based materials caused from 24 to 96h significantly lower proliferation rates in comparison to the controls (p<0.001). For proliferation rates of cells in contact with MTAs and ERRM significant differences were observed throughout the whole observation time for the osteoblasts, but only up to 24h for the human periodontal ligament fibroblasts. CONCLUSION Within the limits of this study the results suggest that the bioceramic root end material is biocompatible, but needs to be investigated in clinical studies before it can be recommended as retrograde sealer in endodontic practice.

Influence of GSM signals on human peripheral lymphocytes: study of genotoxicity.

Exposure to radiofrequency (RF) electromagnetic fields (EMF) is continuously increasing worldwide. Yet, conflicting results of a possible genotoxic effect of RF EMF continue to be discussed. In the present study, a possible genotoxic effect of RF EMF (GSM, 1,800 MHz) in human lymphocytes was investigated by a collaboration of six independent institutes (institutes a, b, c, d, e, h). Peripheral blood of 20 healthy, nonsmoking volunteers of two age groups (10 volunteers 16–20 years old and 10 volunteers 50–65 years old) was taken, stimulated and intermittently exposed to three specific absorption rates (SARs) of RF EMF (0.2 W/kg, 2 W/kg, 10 W/kg) and sham for 28 h (institute a). The exposures were performed in a setup with strictly controlled conditions of temperature and dose, and randomly and automatically determined waveguide SARs, which were designed and periodically maintained by ITIS (institute h). Four genotoxicity tests with different end points were conducted (institute a): chromosome aberration test (five types of structural aberrations), micronucleus test, sister chromatid exchange test and the alkaline comet assay (Olive tail moment and % DNA). To demonstrate the validity of the study, positive controls were implemented. The genotoxicity end points were evaluated independently by three laboratories blind to SAR information (institute c = laboratory 1; institute d = laboratory 2; institute e = laboratory 3). Statistical analysis was carried out by institute b. Methods of primary statistical analysis and rules to adjust for multiple testing were specified in a statistical analysis plan based on a data review before unblinding. A linear trend test based on a linear mixed model was used for outcomes of comet assay and exact permutation test for linear trend for all other outcomes. It was ascertained that only outcomes with a significant SAR trend found by at least two of three analyzing laboratories indicated a substantiated suspicion of an exposure effect. On the basis of these specifications, none of the nine end points tested for SAR trend showed a significant and reproducible exposure effect. Highly significant differences between sham exposures and positive controls were detected by each analyzing laboratory, thus validating the study. In conclusion, the results show no evidence of a genotoxic effect induced by RF EMF (GSM, 1,800 MHz).

Prognostic Influence of Pre-Operative C-Reactive Protein in Node-Negative Breast Cancer Patients

The importance of inflammation is increasingly noticed in cancer. The aim of this study was to analyze the prognostic influence of pre-operative serum C-reactive protein (CRP) in a cohort of 148 lymph node-negative breast cancer patients. The prognostic significance of CRP level for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) was evaluated using univariate and multivariate Cox regression, also including information on age at diagnosis, tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, proliferation index (Ki67) and molecular subtype, as well as an assessment of the presence of necrosis and inflammation in the tumor tissue. Univariate analysis showed that CRP, as a continuous variable, was significantly associated with DFS (P = 0.002, hazard ratio [HR]  = 1.04, 95% confidence interval [CI]  = 1.02–1.07) and OS (P = 0.036, HR  = 1.03, 95% CI  = 1.00–1.06), whereas a trend was observed for MFS (P = 0.111). In the multivariate analysis, CRP retained its significance for DFS (P = 0.033, HR  = 1.01, 95% CI  = 1.00–1.07) as well as OS (P = 0.023, HR  = 1.03, 95% CI  = 1.00–1.06), independent of established prognostic factors. Furthermore, large-scale gene expression analysis by Affymetrix HG-U133A arrays was performed for 72 (48.6%) patients. The correlations between serum CRP and gene expression levels in the corresponding carcinoma of the breast were assessed using Spearmans rank correlation, controlled for false-discovery rate. No significant correlation was observed between CRP level and gene expression indicative of an ongoing local inflammatory process. In summary, pre-operatively elevated CRP levels at the time of diagnosis were associated with shorter DFS and OS independent of established prognostic factors in node-negative breast cancer, supporting a possible link between inflammation and prognosis in breast cancer.

Psychosocial Care Needs of Melanoma Survivors: Are They Being Met?

Patients who have survived malignant melanoma for more than five years may lack the opportunity to talk about their burden. As a consequence their psychosocial care needs remain undetected and available supportive interventions may not be utilised. Therefore, the psychosocial burden of this patient group needs to be assessed using specific screening instruments. The aim of this study was to investigate the psychosocial burden of long-term melanoma survivors, their psychosocial care needs and the determinants of these needs. We wanted to find out if the use of professional support corresponds to the care needs defined by experts. Using the cancer registry of Rhineland-Palatinate, melanoma patients diagnosed at least 5 years before the survey were contacted by physicians. N = 689 former patients completed the Hornheide Questionnaire (short form HQ-S) to identify psychosocial support need (scale cut off ≥ 16 or item-based cut-off score) and the potential psychosocial determinants of these needs. Additionally, they were asked about their utilisation of the professional support system. More than one third (36%) of them was in need for professional psychosocial support. The highest burden scores concerned worry about tumour progression. Younger age (< 50), higher general fatigue, higher symptom burden, lower general health, negative social interactions and unfulfilled information needs were significant predictors of the need for psychosocial intervention. Related to the percentage of survivors identified as ‘in need’, the professional support system was underused. Further studies should investigate whether using the HQ-S to routinely identify burdened melanoma patients could lead to better fulfilment of their intervention needs, ultimately enhancing health-related quality of life.

Cardiotoxicity of Mitoxantrone Treatment in a German Cohort of 639 Multiple Sclerosis Patients

Background and Purpose The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. Methods Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. Results None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. Conclusions The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically).

A randomized trial comparing conventional cytology to liquid-based cytology and computer assistance.

Liquid‐based cytology (LBC) has replaced conventional cytology (CC) for cervical cancer screening in some countries. However, it remains unclear whether LBC is superior to CC. A randomized controlled trial was conducted between August 2007 and March 2009 in Germany to compare LBC, alone and in combination with computer‐assisted imaging technology (CAS), to CC in the detection of histologically confirmed cervical intraepithelial neoplasia (CIN). The main outcome measures were detection rates, relative sensitivities, positive predictive values (PPVs) and relative PPVs comparing LBC without and with CAS to CC. Primary histological outcome was CIN2 or higher. Included were 20,627 women participating in opportunistic cervical cancer screening at 20 gynecologic practices. The practices were randomized weekly to use LBC (n = 11,331) or CC (n = 9,296). Patients with positive findings were invited to expert colposcopy. The relative sensitivity of LBC versus CC using the CIN2+ cut‐off was 2.74 (95% confidence interval [CI] 1.66–4.53). The relative sensitivity of LBC/CAS versus CC for CIN2+ was 3.17 (95% CI 1.94–5.19). The PPV of LBC and CC for CIN2+ was 48% and 38%, respectively. The PPV ratio did not differ significantly from unity. Differences between LBC and CC were smaller in some sensitivity and subgroup analyses; however, relative sensitivity of LBC remained increased. LBC without and with CAS compared with CC under the field conditions of an opportunistic screening system had a significantly higher sensitivity for the detection of CIN without deterioration of PPVs. Additional use of CAS did not further improve sensitivity of LBC.

Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study

The identification of prognostic markers has clinical implications in epithelial ovarian carcinoma (EOC). Here, we studied markers for proliferation (Ki-67), endocrine regulation [progesterone receptor (PR), estrogen receptor (ER)], and invasion [urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1)]. All patients with available follow-up information and EOC tissue, who were treated at our institution between 1997 and 2004, were enrolled in the present study. Expression of Ki-67, PR and ER was determined by immunohistochemical analyses. uPA and PAI-1 antigen levels were determined using enzyme‑linked immunosorbent assays. One hundred and eight patients entered the present study. The median follow-up time was 43.3 (range 11.4-68.0) months. In multivariable Cox regression analyses, Ki-67 expression showed an independent negative impact on disease-free survival (DFS) and overall survival (OS) [hazard ratio (HR) for DFS, 11.5; 95% confidence interval (CI), 2.64-49.7; p=0.001 and HR for OS, 21.2; 95% CI, 9.9-113.1; p<0.001]. After cut-off optimization, PR expression showed an independent positive impact on prognosis (HR for DFS, 0.15; 95% CI, 0.03-0.68; p=0.014 and HR for OS, 0.13; 95% CI, 0.03‑0.68; p=0.016). Furthermore, postoperative residual tumor burden and completeness of chemotherapy determined the prognosis. ER, uPA and PAI-1 were not associated with survival. PR and ER, and postoperative residual tumor burden and tumor stage showed a strong correlation in an explorative Spearmans rank correlation coefficient (rho=0.759 and rho=0.426, respectively). Ki-67 and cut-off optimized PR are independently associated with the prognosis of EOC. Further prospective studies are warranted to confirm these associations and to elucidate the underlying mechanisms.

Phosphodiesterase 10A in the rat pineal gland: localization, daily and seasonal regulation of expression and influence on signal transduction.

The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal spiny projection neurons and represents a therapeutic target for the treatment of psychotic symptoms. As reported previously [J Biol Chem 2009; 284:7606–7622], in this study PDE10A was seen to be additionally expressed in the pineal gland where the levels of PDE10A transcript display daily changes. As with the transcript, the amount of PDE10A protein was found to be under daily and seasonal regulation. The observed cyclicity in the amount of PDE10A mRNA persists under constant darkness, is blocked by constant light and is modulated by the lighting regime. It therefore appears to be driven by the master clock in the suprachiasmatic nucleus (SCN). Since adrenergic agonists and dibutyryl-cAMP induce PDE10A mRNA, the in vitro clock-dependent control of Pde10a appears to be mediated via a norepinephrine → β-adrenoceptor → cAMP/protein kinase A signaling pathway. With regard to the physiological role of PDE10A in the pineal gland, the specific PDE10A inhibitor papaverine was seen to enhance the adrenergic stimulation of the second messenger cAMP and cGMP. This indicates that PDE10A downregulates adrenergic cAMP and cGMP signaling by decreasing the half-life of both nucleotides. Consistent with its effect on cAMP, PDE10A inhibition also amplifies adrenergic induction of the cAMP-inducible gene arylalkylamine N-acetyltransferase (Aanat) which codes the rate-limiting enzyme in pineal melatonin formation. The findings of this study suggest that Pde10a expression is under circadian and seasonal regulation and plays a modulatory role in pineal signal transduction and gene expression.