Changes in the prognostic values of modern cardiovascular biomarkers in relation to duration of diabetes mellitus.

BACKGROUND: Based on the complex pathophysiology of type 2 diabetes and atherosclerosis we hypothesized a dynamic change in prognostic value of cardiovascular biomarkers over time. METHODS: In this prospective study 746 patients with type 2 diabetes mellitus, being followed up for 60 months were analysed. The primary endpoint was defined as unplanned hospitalization for cardiovascular disease or death. Beside others, especially the prognostic performance of the biomarkers of interest (GDF-15, NT-proBNP, hs-TnT) was evaluated in relation to quartiles of diabetes duration. RESULTS: In patients having a diabetes duration below 7 years lnGDF-15 (HR 2.84; p < 0.01) and lnhs-TnT (HR 2.96; p < 0.01) were significant predictors of the primary endpoint. LnAge (HR 40.01; p < 0.01) and lnNT-proBNP (HR 1.56; p = 0.03) were significant predictors in patients with a diabetes duration between 7 and 12 years. In the third quartile (diabetes duration 12-22 years) lnurinary albumin to creatinine ratio (HR 1.25; p = 0.005) and lnNT-proBNP (HR 2.13, p < 0.001) predicted the endpoint. In patients with a diabetes duration above 22 years, lnAge (HR 75.35; p = 0.001) and lnNT-proBNP (HR 2.0; p < 0.01) were the only significant predictors of the endpoint. CONCLUSION: Prognostic power of cardiovascular biomarkers changes dynamically in relation to duration of type 2 diabetes mellitus. In patients with shorter duration of the disease markers of subclinical cardiovascular dysfunction and inflammation perform better than markers of systemic advanced organ dysfunction and cardiovascular disease.

Argyrophilic grain disease in individuals younger than 75 years: clinical variability in an under-recognized limbic tauopathy.

BACKGROUND AND PURPOSE: Argyrophilic grain disease (AGD) is a limbic-predominant 4R-tauopathy. AGD is thought to be an age-related disorder and is frequently detected as a concomitant pathology with other neurodegenerative conditions. There is a paucity of data on the clinical phenotype of pure AGD. In elderly patients, however, AGD pathology frequently associates with cognitive decline, personality changes, urine incontinence and cachexia. In this study, clinicopathological findings were analysed in individuals younger than 75. METHODS: Patients were identified retrospectively based on neuropathological examinations during 2006-2017 and selected when AGD was the primary and dominant pathological finding. Clinical data were obtained retrospectively through medical records. RESULTS: In all, 55 patients (2% of all examinations performed during that period) with AGD were identified. In seven cases (13%) AGD was the primary neuropathological diagnosis without significant concomitant pathologies. Two patients were female, median age at the time of death was 64 years (range 51-74) and the median duration of disease was 3 months (range 0.5-36). The most frequent symptoms were progressive cognitive decline, urinary incontinence, seizures and psychiatric symptoms. Brain magnetic resonance imaging revealed mild temporal atrophy. CONCLUSIONS: Argyrophilic grain disease is a rarely recognized limbic tauopathy in younger individuals. Widening the clinicopathological spectrum of tauopathies may allow identification of further patients who could benefit from tau-based therapeutic strategies.

Increased risk of death associated with the use of proton-pump inhibitors in patients with dementia and controls - a pharmacoepidemiological claims data analysis.

BACKGROUND AND PURPOSE: The use of proton-pump inhibitors (PPIs) was reported to be associated with increased mortality risk and has been proposed as a potential risk factor for neurodegenerative diseases. We aimed to assess the impact of PPI use on survival in patients with dementia as compared with controls. METHODS: This register-based control-matched cohort study included 28 428 patients with dementia ascertained by the prescription of antidementia drugs and two control individuals matched by sex, age and area of residence for each patient with dementia during the study period from 1 January 2005 to 30 June 2016. Cumulative defined daily doses (DDDs) of PPIs were extracted from the health insurance prescription registries. A multivariate Cox regression model for non-proportional hazards was used to analyse mortality risk in dependence of PPI exposure, which was limited to 1 year preceding the date of cohort entry (index date) in order to avoid immortal time bias. RESULTS: The PPI exposure of 100 DDDs in the year before the index date was associated with an increased mortality risk in patients with dementia (adjusted hazard ratio, 1.07; 95% confidence intervals, 1.03-1.12), but also in controls (adjusted hazard ratio, 1.47; 95% confidence intervals, 1.31-1.64). The mortality risk in relation to PPI use was significantly lower in patients with dementia as compared with controls (P < 0.0001) and highest in the first 2 years after the index date in both cohorts. CONCLUSIONS: Our findings promote more stringent pharmacovigilance strategies to avoid PPI use in cases lacking a clear indication for therapy or where potential risks outweigh the benefits.

Imbalance between plasma double-stranded DNA and deoxyribonuclease activity predicts mortality after out-of-hospital cardiac arrest.

AIM: Despite an increased rate of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA) patients, almost half of patients do not survive up to hospital discharge. Understanding pathophysiological mechanisms of post-cardiac arrest syndrome is essential for developing novel therapeutic strategies. During systemic inflammatory responses and concomitant cell death, double-stranded (ds) DNA is released into circulation, exerting pro-inflammatory effects. Deoxyribonuclease (DNase) degrades dsDNA. The role of DNase activity in OHCA survivors and impact on clinical outcome has not been analyzed yet. METHODS: In a prospective, single-center study, dsDNA and DNase activity were determined at hospital admission (acute phase) and 24 h (subacute phase) after ROSC. The ratio between dsDNA levels and DNase activity was calculated to determine the extent of dsDNA release in relation to the patients' capacity of degradation. Thirty-day mortality was defined as study end point. RESULTS: We enrolled 64 OHCA survivors, of whom 26.6% (n = 17) died within 30 days. A peak of circulating dsDNA was observed at admission which decreased within 24 h. DNase activity did not differ between acute and subacute phase, while dsDNA load per DNase activity significantly decreased. The ratio between dsDNA levels and DNase activity in the subacute phase was the strongest predictor of 30-day mortality with an adjusted HR per 1 SD of 3.59 (95% CI, 1.80-7.18, p < 0.001). CONCLUSION: Disproportionally increased dsDNA levels uncompensated by DNase activity are a strong predictor of mortality in OHCA survivors. This pilot study points to a potentially protective effect of DNase activity in patients undergoing cardiac arrest.

Targeted multiple biomarker approach in predicting cardiovascular events in patients with diabetes.

OBJECTIVE: We hypothesised that biomarkers representing different pathophysiological pathways of atherosclerosis namely growth differentiation factor 15 (GDF-15), N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT) could enhance cardiovascular risk prediction in patients with type 2 diabetes mellitus. METHODS: This is a prospective study in 746 patients with type 2 diabetes mellitus, who were followed up for 60 months. The primary endpoint was defined as unplanned hospitalisation for cardiovascular disease or death. The prognostic performance of the biomarkers of interest (GDF-15 in comparison with NT-proBNP and hs-TnT) was evaluated in univariate as well as in stepwise Cox regression models. HRs are presented per standard unit increase. RESULTS: The primary endpoint was registered in 171 patients (22.9%). In univariate Cox regression models, GDF-15 as well as hs-TnT provided significant prognostic information. Even after adjusting for established cardiovascular risk factors, GDF-15, hs-TnT and NT-proBNP remained strong independent predictors of the endpoint (logGDF-15: HR 1.37, p<0.01, CI 1.12 to 1.68; loghs-TnT: HR 1.43, p<0.01, CI 1.13 to 1.1.82; logNT-proBNP: HR 1.45, p<0.01, CI 1.26 to 1.66). The number of elevated markers showed a strong complementarity to predict future long-term risk. Adding hs-TnT and GDF-15 to a zero model already including NT-proBNP led to a net reclassification improvement (NRI) of 33.6% (CI 16.0% to 50.8%, NRI for patients with event: 11.1% CI -4.7% to 26.6%, for patients without event: 22.5% CI 13.6% to 30.5%). CONCLUSIONS: GDF-15 and hs-TnT are strong independent cardiovascular biomarkers augmenting the predictive value of NT-proBNP in patients with diabetes.

Gender-related impact on outcomes of high density lipoprotein in acute ST-elevation myocardial infarction.

BACKGROUND AND AIMS: There is rising evidence that cardioprotective functions of high-density lipoprotein (HDL) have significant impact on clinical outcomes. ST-elevation myocardial infarction (STEMI) represents a high-risk vascular condition. Whether higher HDL-cholesterol concentrations in women correspond to protective anti-oxidant properties in the setting of STEMI is unknown. METHODS: We prospectively assessed gender related differences in the anti-oxidant function of HDL, and the impact of HDL properties on mortality in 242 women and men with STEMI. Blood samples to determine HDL function and sex hormone levels were collected during primary percutaneous coronary intervention. RESULTS: Patients were stratified according to preserved anti-oxidant HDL function (HDL oxidant index (HOI) < 1) and pro-oxidant HDL (HOI≥1). Despite higher serum levels of HDL-cholesterol in postmenopausal women (48 mg/dl, IQR 42-54, versus 39 mg/dl, IQR33-47, p < 0.001 in men), the proportion of patients with pro-oxidant HDL was not different between women (35%) and men (46%, p = 0.132). Kaplan-Meier analysis revealed higher cardiovascular mortality in both women (p = 0.021) and men (p = 0.045) with pro-oxidant HDL. We identified pro-oxidant HDL as strong and independent predictor of cardiovascular mortality with an adjusted HR of 8.33 (95% CI, 1.55-44.63; p = 0.013) in women and with an adjusted HR of 5.14 (95% CI, 1.61-16.42; p = 0.006) in men. Higher levels of free sex hormones (estradiol and testosterone) were associated with pro-oxidant HDL. HDL-cholesterol levels showed no association with mortality (HR in women 1.03, 95% CI 0.96-1.11, p = 0.45 and HR in men 0.99, 95% CI 0.94-1.05, p = 0.72). CONCLUSIONS: Total HDL-cholesterol serum levels were not associated with mortality in STEMI patients. Pro-oxidant HDL was a strong and independent predictor of mortality in women and men with STEMI. The present study provides a link between sex hormones, HDL function and clinical events in STEMI patients. In clinical practice and future clinical trials, anti-oxidant properties of HDL rather than total HDL serum levels should be used for risk stratification.

Peri-interventional endothelin--a receptor blockade improves long-term outcome in patients with ST-elevation acute myocardial infarction.

Endothelin (ET)-1 is a pro-fibrotic vasoconstrictive peptide causing microvascular dysfunction and cardiac remodelling after acute ST-elevation myocardial infarction (STEMI). It acts via two distinct receptors, ET-A and ET-B, and is involved in inflammation and atherogenesis. Patients with posterior-wall STEMI were randomly assigned to intravenous BQ-123 at 400 nmol/minute (min) or placebo over 60 min, starting immediately prior to primary percutaneous coronary intervention (n=54). Peripheral blood samples were drawn at baseline as well as after 24 hours and 30 days. Myeloperoxidase (MPO), as a marker of neutrophil activation and matrix metalloproteinase 9 (MMP-9), a marker of extracellular matrix degradation were measured in plasma. Clinical follow-up was conducted by an investigator blinded to treatment allocation over three years. During the median follow-up period of 3.6 years (interquartile range [IQR] 3.3-4.1) we observed a longer event-free survival in patients randomised to receive BQ-123 compared with patients randomised to placebo (mean 4.5 years (95% confidence interval: 3.9-5) versus mean 3 years (2.2-3.7), p=0.031). Patients randomised to ET-A receptor blockade demonstrated a greater reduction of MPO levels from baseline to 24 hours compared to placebo-treated patients (-177 ng/ml (IQR 103-274) vs -108 ng/ml (74-147), p=0.006). In addition, a pronounced drop in MMP-9 levels (-568 ng/ml (44-1157) vs -117 ng/ml (57-561), p=0.018) was observed. There was no significant difference in amino-terminal propetide of pro-collagen type III levels. In conclusion, short-term administration of BQ-123 leads to a reduction in MPO, as well as MMP-9 plasma levels and to a longer event-free survival in patients with STEMI.

Effectiveness of bevacizumab for radiation-induced cerebral necrosis in children.

INTRODUCTION: Bevacizumab has been reported to effectively reduce cerebral edema caused by radiation therapy. However, only limited data with a short follow-up in tumor patients are available so far. PATIENTS AND METHODS: Two children suffering from hemorrhage from arteriovenous malformation (AVM) have been treated with stereotactic radiotherapy and developed radiation-induced cerebral edema with deteriorating neurological status despite maximized steroid therapy. Bevacizumab administration at 5 mg/kg body weight was initiated every 2 weeks. RESULTS: Bevacizumab treatment rapidly ameliorated the neurological deficits, malignant edema and prevented catastrophic complications. Corticoid therapy could be reduced and discontinued. However, after 18 months, both patients showed identical or worse neurological status than before bevacizumab therapy. AVM radiation therapy had been successful to completely obliterate AVMs. DISCUSSION: In our limited experience, bevacizumab may be an effective and safe option for rescue therapy for malignant cerebral edema on the basis of radiation-induced necrosis especially in patients who experience rapid deterioration despite corticoid therapy and/or intolerable steroid side effects. Despite the fact that functional improvement could not be achieved in long-term outcome patients significantly stabilized and improved during periods of acute deterioration. In order to determine the long-term effectiveness of bevacizumab further investigation in placebo-controlled studies with a higher number of patients are required.

Pulmonary histoplasmosis in three Austrian travelers after a journey to Mexico.

Three Austrian travelers (a 37-year-old woman, a 47-year-old woman and a 47-year-old man) presented with fever, dyspnea, thoracodynia, cephalea, arthralgia and fatigue 4 weeks after visiting a bat cave in Mexico. Computed tomography of the lungs showed bilateral nodular infiltrates in all three patients and enlarged mediastinal lymph nodes in two patients. In all patients, specific IgM antibodies against Histoplasma capsulatum could be detected. After treatment with itraconazole 200 mg q.d. orally for 2 months, the patients had no further complaints and the pulmonary infiltrates had resolved.

123I-IMT SPECT for evaluation of the response to radiation therapy in high grade gliomas: a feasibility study.

Assessing response to radiation therapy in patients with high grade gliomas is needed upon making decisions toward further therapy strategies. Currently used standard imaging tools such as CT and MRI are not sensitive enough to detect early therapy effects. We prospectively investigated if single photon emission computed tomography (SPECT) using radiolabelled amino acid derivate (123)I-methyltyrosine (IMT) would be useful for this aim. 10 patients with histologically proven high grade gliomas, who were candidates for radiation therapy, were enrolled in this investigation. All patients were examined by IMT SPECT before radiation therapy and 4 weeks after the initiation of the hypofractionated application of 40 Gy. Patients were followed up for 39 months; the tumours to background ratios (T/B) for IMT under/before radiation therapy were correlated to survival times. Initially, SPECT depicted an abnormal intratumoural IMT uptake in all patients (mean T/B ratios 1.37-1.87). In four out of 10 patients, the mean T/B ratios decreased by more than 10% under radiation therapy. In six other patients, the BQ decreased by less than 10% or increased. There were no significant correlations between the degree of changes in T/B and survival (r = -0.1, p = 0.973). Serial IMT SPECT measurements allow detection of changes in amino acid accumulation in high-grade gliomas under radiation therapy. However, these changes seem to possess no prognostic value in respect to survival prediction.

Image guided respiratory gated hypofractionated Stereotactic Body Radiation Therapy (H-SBRT) for liver and lung tumors: Initial experience.

To evaluate our initial experience with image guided respiratory gated H-SBRT for liver and lung tumors. The system combines a stereoscopic x-ray imaging system (ExacTrac X-Ray 6D) with a dedicated conformal stereotactic radiosurgery and radiotherapy linear accelerator (Novalis) and ExacTrac Adaptive Gating for dynamic adaptive treatment. Moving targets are located and tracked by x-ray imaging of implanted fiducial markers defined in the treatment planning computed tomography (CT). The marker position is compared with the position in verification stereoscopic x-ray images, using fully automated marker detection software. The required shift for a correct, gated set-up is calculated and automatically applied. We present our acceptance testing and initial experience in patients with liver and lung tumors. For treatment planning CT and Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) as well as magnetic resonance imaging (MRI) taken at free breathing and expiration breath hold with internal and external fiducials present were used. Patients were treated with 8-11 consecutive fractions to a dose of 74.8-79.2 Gy. Phantom tests demonstrated targeting accuracy with a moving target to within +/-1 mm. Inter- and intrafractional patient set-up displacements, as corrected by the gated set-up and not detectable by a conventional set-up, were up to 30 mm. Verification imaging to determine target location during treatment showed an average marker position deviation from the expected position of up to 4 mm on real patients. This initial evaluation shows the accuracy of the system and feasibility of image guided real-time respiratory gated H-SBRT for liver and lung tumors.

Glioma assessment using quantitative blood volume maps generated by T1-weighted dynamic contrast-enhanced magnetic resonance imaging: a receiver operating characteristic study.

PURPOSE: To investigate the use of blood volume maps in the non-invasive separation of glioma grades. MATERIAL AND METHODS: T1-weighted quantitative dynamic contrast-enhanced magnetic resonance imaging was used to quantify the fractional intratumoral blood volume of 41 gliomas (World Health Organization (WHO) grades II-IV). Two methods, mean fractional intratumoral blood volume determination and a system based on thresholds for extracting the tumor pixels with the highest vascularization from the blood volume maps, were investigated by means of receiver operating characteristic (ROC) analysis. The thresholds were adjusted using the ROC curve area calculated using the trapezoid method. RESULTS: The ability to separate grade II (WHO) gliomas from grades III-IV was nearly the same for both methods (ROC curve area 0.941 (threshold) versus 0.932 (mean value)) and significantly greater than the ability to separate grade IV (WHO) gliomas from grades II-III (ROC curve area 0.792 (threshold) versus 0.787 (mean value)). The best correspondence with WHO glioma grading was achieved using thresholds corresponding to only the 5.2% of tumor voxels with the largest blood volume for separating grade II gliomas and 4% for separating grade IV gliomas. CONCLUSION: Use of the optimized threshold resulted in matching with the WHO grading system in 74% of cases.

[Brain metastases of lung cancer]. / Hirnmetastasen beim Lungenkarzinom.

Cerebral metastases are a frequent complication of lung cancer. They often determine patients' prognosis and need urgent therapeutic intervention. Based on histologic type, former therapies, age and performance of the patient, the number of cerebral lesions and the extracerebral tumour activity, individualized treatments are applied. For patients who suffer from non-small cell lung cancer and a single CNS lesion the best results can be achieved if they are surgically resected or receive radiosurgery. Their survival time can be markedly increased in comparison to patients who undergo whole brain irradiation. If multiple metastases are seen in CT or MRI, whole brain irradiation is the therapy to choose. Furthermore it should be initiated if small cell lung cancer metastasizes to the brain. More aggressive local treatment options appear promising, but a clear role for them has not yet been defined. Systemic chemotherapy gains more attention in the treatment of small and non-small cell lung cancer with brain metastases. How to increase the efficacy through simultaneous application of chemo- and radiotherapy is tested in current trials. This article gives an overview on clinical presentation and diagnosis of cerebral metastases in lung cancer and reviews current treatment options.

Adaptation of a commercial ELISA for the detection of antibodies against Neospora caninum in bovine milk.

The aim of the present study was to determine whether a commercially available ELISA could be used to examine bovine milk for antibodies against Neospora caninum. In an initial titration experiment, a milk dilution of 1:2 was found optimal to obtain milk results that were linearly correlated to those obtained with corresponding sera. This dilution was then used to examine 791 milk samples from N. caninum infected herds in the commercial ELISA. Milk results of individual animals were compared with those obtained by the same ELISA for the corresponding serum samples. The linear correlation between milk and serum antibody results of individual animals was characterized by R2 = 0.702. Multiple linear regression indicated that the later the stage of lactation at which an animal was sampled, the higher the milk ELISA result was as compared to the serum ELISA result. The examination of the two-graph receiver operating characteristics revealed an optimal cut-off of 0.261 to obtain similar results in the examination of milk and serum. With this cut-off, the test had a sensitivity and specificity relative to the serum results of 90%. The milk-based commercial ELISA classified more aborting dams as positive than the serum-based ELISA with this cut-off. The milk ELISA may be a valuable tool to assess the herd status with regard to abortion caused by N. caninum.

Regional distribution of bovine Neospora caninum infection in the German state of Rhineland-Palatinate modelled by Logistic regression.

To obtain a rapid overview over the distribution of bovine Neospora caninum-infections in the German state of Rhineland-Palatinate, an ELISA to determine specific bovine antibodies against a p38 surface antigen of N. caninum tachyzoites was modified to examine bulk milk samples from cattle herds. Experimental bulk milk samples were used to demonstrate that the seroprevalence in a group of animals can be estimated with this ELISA. A cut-off was selected for the specific detection of herds having a seroprevalence > or =10%. About 90% of the dairy herds located in Rhineland-Palatinate were examined. An overall prevalence of bulk milk-positive herds of 7.9% (95% confidence interval 7.0-8.9%), respectively, was determined. Major regional differences in the distribution of bulk milk-positive herds were observed. Prevalences were higher in regions with an increased degree of urbanisation. Logistic regression was applied to model the prevalence of bulk milk-positive herds on a district and city level. Variables describing the dog density, mean temperature in July, mean temperature in January and the total yearly precipitation in districts and cities were able to explain most of the observed variability in the regional prevalences. Our results provide evidence that in addition to risk factors related to individual farms also risk factors related to the farm location such as dog density in the surrounding and climate factors are important in the epidemiology of bovine neosporosis.

Radiation-induced apoptosis in human non-small-cell lung cancer cell lines is secondary to cell-cycle progression beyond the G2-phase checkpoint.

PURPOSE: To characterize the relationship between cell-cycle progression and radiation-induced apoptosis in NSCLC cell lines with different p53 status. MATERIALS AND METHODS: Cell lines with functional (H460, A549) and non-functional p53 (H661 and H520) were irradiated with 20 Gy. Multiparameter flow-cytometry was used to follow the progression of synchronized cells through the cell cycle after irradiation. RESULTS: Delayed apoptosis was observed after cell-cycle progression beyond the G2 block, either in the late G2/M-phase of the same cell cycle being irradiated (H661, H520) or in the G1-phase of the subsequent cell cycle (H460, A549). The apoptotic fraction in H661 and H520 was 60-80% at 144h after irradiation, higher than in A549 and H460 (5 and 35%, respectively). As an alternative to apoptosis in cells cycling beyond the G2 restriction point, hyperploid cells were generated by all cell lines. Inhibition of cell-cycle progression through the G2/M-phase efficiently reduced the induction of late apoptosis. After irradiation in S-phase, 50-60% of cells with functional p53 remained arrested at the G2 restriction point until 144 h post-irradiation, while only 20% of the H661 or H520 did so. CONCLUSIONS: These data characterize radiation-induced apoptosis in NSCLC cell lines as a removal pathway of clonogenically inactivated cells secondary to cell-cycle progression beyond G2/M, and is unlikely to be a critical factor for cellular radiation sensitivity.

p38-avidity-ELISA: examination of herds experiencing epidemic or endemic Neospora caninum-associated bovine abortion.

An enzyme-linked immunosorbent assay (ELISA) was established to measure the avidity of bovine IgG directed against p38, a surface antigen (NCSRS2) of Neospora caninum tachyzoites. In the sera of dams intravenously infected with N. caninum NC-1, the p38-specific avidity increased from initially below 40% up to avidity indices between 50 and 80% after days 23 and 91 p.i. The p38-avidity-ELISA was used to examine various herds that had experienced endemic and epidemic N. caninum-associated bovine abortions. In herds with endemic abortion, generally high avidity indices of N. caninum-specific IgG were detected. This finding and the observation of an association between the seropositivity of dams and that of their offspring suggested a predominantly vertical transmission of the parasite among the animals of these herds, thus indicating chronic infection of these cattle. In contrast, for herds experiencing epidemic abortion: (i) an association regarding seropositivity of dams and their daughters could not be shown and (ii) a generally low avidity of p38-specific IgG in the sera from aborting dams was determined. This indicates recent postnatal transmission of N. caninum in these herds. A linear regression model explaining the avidity of p38-specific IgG was significantly influenced by the time span between sampling and the occurrence of the first abortion of the epidemic in herds with an N. caninum-associated abortion storm. Another factor significantly contributing to the model was the proportion of dams at risk that had aborted in the herds (i.e. the severity of the abortion epidemic). A possible explanation for this observation is that herds experiencing heavy abortion are sampled earlier after the onset of the epidemic than others that have a less severe abortion storm.

Bovine neosporosis: immunoblot improves foetal serology.

The purpose of the study is the comparative evaluation of the immunofluorescent antibody test (IFAT) and an immunoblot (IB) test for the examination of foetal fluids for specific antibodies against Neospora caninum. Peritoneal and pleural fluids as well as abomasal contents were analysed. The results of the serological examinations were compared to those obtained by histological, immunohistochemical, and PCR analysis of foetal tissues as well as to the results of maternal serological examinations. Fluids were used undiluted in the IB and reactions against six immunodominant antigens were recorded. When the recognition of at least two immunodominant antigens was regarded as positive, the agreement of the IB with other diagnostic methods was good to moderate as characterised by kappa-values of 0.76 (histology/immunohistochemistry), 0.69 (maternal serology) and 0.54 (PCR on foetal tissues). The IB results agreed better with the results of the other diagnostic methods than those of the IFAT. The higher relative sensitivity of the IB was regarded as the main reason for the better agreement. However, also the specificity of the IB was superior to that of the IFAT in relation to histology/immunohistochemistry, maternal serology and PCR.

[Current and future strategies in interdisciplinary treatment of medulloblastomas, supratentorial PNET (primitive neuroectodermal tumors) and intracranial germ cell tumors in childhood]. / Aktuelle und zukünftige Strategien in der interdisziplinären Therapie von Medulloblastomen, supratentoriellen PNET und intrakraniellen Keimzelltumoren im Kindesalter.

BACKGROUND: The chances for cure in medulloblastoma, supratentorial primitive neuroectodermal tumors (stPNET) and intracranial germ cell tumors have decisively improved within the last decades. Today long-term survival in the range between 60% and 80% and more than 90%, respectively, can be achieved. The low incidence of brain tumors in childhood and the necessity for optimal patient care has led to the fact that more than 90% of children are treated within national and international controlled studies today in order to assure a constant improvement of therapeutic outcome. Recent developments in neurosurgery achieved complete tumor resections in the majority of children at a low risk for morbidity and mortality. METHODS: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival. RESULTS: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome. CONCLUSIONS: The therapeutic endeavors of all those caring for children are aiming to study modifications of the therapeutic components in the interdisciplinary approach in order to optimize the therapeutic strategies. In future the affected children and young adolescents should be accrued for the forthcoming cooperative, prospective trial HIT 2000 and ongoing trial SIOP CNS GCT 96, respectively, in order to provide the body of data supporting the selection of novel and optimized approaches for future treatment strategies.

Comparison of dynamic contrast-enhanced MRI with WHO tumor grading for gliomas.

Assessment of vascular proliferation as an important grading criterion has been employed in both the histologic and the radiologic characterization of gliomas with encouraging results. Perfusion in gliomas can be measured by dynamic contrast-enhanced magnetic resonance imaging (dMRI). The goal of this study was to develop a model for simultaneously quantifying the fractional volumes of different tissue compartments of gliomas by dMRI. A modified method for evaluating dynamic contrast-enhanced MR images is presented which simultaneously determines the fractional vascular, interstitial, and cellular volumes of gliomas. This method differs from techniques used in other studies in that it is based on a three-compartment model: a single blood compartment and two interstitial ones. The fractional volume maps are compared with the WHO glioma grading. The results show the method to be feasible. Using cerebral blood volume (CBV), dMRI grading showed a correspondence with WHO grading in 83% of the cases (20/24 gliomas WHO grades II-IV). The use of interstitial volume maps can also be helpful, for instance, in differentiating gliomas from other brain tumors. As a supplement to conventional MRI, dynamic MR techniques thus provide a useful tool for improving in vivo glioma characterization.