Würzburg, Germany
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Blinatumomab can induce a complete haematological remission in patients in 46.6% with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) resulting in a survival benefit when compared with chemotherapy. Only bone marrow blast counts before therapy have shown a weak prediction of response. Here we investigated the role of regulatory T cells (Tregs), measured by CD4/CD25/FOXP3 expression, in predicting the outcome of immunotherapy with the CD19-directed bispecific T-cell engager construct blinatumomab. Blinatumomab responders (n=22) had an average of 4.82% Tregs (confidence interval (CI): 1.79–8.34%) in the peripheral blood, whereas non-responders (n=20) demonstrated 10.25% Tregs (CI: 3.36–65.9%). All other tested markers showed either no prediction value or an inferior prediction level including blast BM counts and the classical enzyme marker lactate dehydrogenase. With a cutoff of 8.525%, Treg enumeration can identify 100% of all blinatumomab responders and exclude 70% of the non-responders. The effect is facilitated by blinatumomab-activated Tregs, leading to interleukin-10 production, resulting in suppression of T-cell proliferation and reduced CD8-mediated lysis of ALL cells. Proliferation of patients' T cells can be restored by upfront removal of Tregs. Thus, enumeration of Treg identifies r/r ALL patients with a high response rate to blinatumomab. Therapeutic removal of Tregs may convert blinatumomab non-responders to responders.Leukemia advance online publication, 24 February 2017; doi:10.1038/leu.2017.41. © 2017 The Author(s)


Geiger H.,Goethe University Frankfurt | Wanner C.,Universitatsklinik Wurzburg
CKJ: Clinical Kidney Journal | Year: 2012

Although the following text will focus on magnesium in disease, its role in healthy subjects during physical exercise when used as a supplement to enhance performance is also noteworthy. Low serum magnesium levels are associated with metabolic syndrome, Type 2 diabetes mellitus (T2DM) and hypertension; consequently, some individuals benefit from magnesium supplementation: increasing magnesium consumption appears to prevent high blood pressure, and higher serum magnesium levels are associated with a lower risk of developing a metabolic syndrome. There are, however, conflicting study results regarding magnesium administration with myocardial infarction with and without reperfusion therapy. There was a long controversy as to whether or not magnesium should be given as a first-line medication. As the most recent trials have not shown any difference in outcome, intravenous magnesium cannot be recommended in patients with myocardial infarction today. However, magnesium has its indication in patients with torsade de pointes and has been given successfully to patients with digoxin-induced arrhythmia or life-threatening ventricular arrhythmias. Magnesium sulphate as an intravenous infusion also has an important established therapeutic role in pregnant women with pre-eclampsia as it decreases the risk of eclamptic seizures by half compared with placebo. © The Author 2012.


Despite the fact that only 2 % of diabetic patients need renal replacement therapy (RRT) during their lifetime, the large group of type 2 diabetics in particular accounts for a large percentage of dialysis patients in industrialized countries. Generally, all three different renal replacement treatments, hemodialysis, peritoneal dialysis and transplantation, can be appropriate for diabetic patients. Because of the strong influence on the quality of life and also life span, all patients have to be duly informed and as early as possible. The different RRTs have to be considered as additive to each other (integrative renal care). Preparations for renal replacement should be completed in time in order to avoid urgent initiation of therapy which results in increased morbidity and mortality. All three renal replacement modalities exhibit specific treatment-related complications, which have to be known by the patients to be able to give informed consent. The most frequent causes of death for all RRTs are still cardiovascular events followed by infections. © 2013 Springer-Verlag Berlin Heidelberg.


Currently, preparations containing native allergens or allergoids are used predominantly in allergen-specific immunotherapy (SIT) of inhaled allergies. The safety and efficacy of these preparations has been demonstrated. However, their reproducible production and standardisation requires substantial effort. Besides this, improved efficacy is often associated with higher doses and an increase in adverse events. The production of recombinant allergens could make SIT preparations more precisely definable, purer, more reproducible, safer and more efficacious. Furthermore, a more specific and individually tailored therapy would be conceivable. These effects could be further amplified by modification to hypoallergenic variants and peptides, or by the addition of adjuvants. Results of clinical trials with recombinant grass, birch and ragweed pollen, as well as with cat hair allergens have already been published. Particularly broad clinical experience exists for recombinant birch and grass pollen preparations, and results are promising for commercial application. Taken as a whole, this new technology can both improve the therapy of allergic diseases and deepen the understanding of the molecular mechanisms of SIT. © 2013 Springer-Verlag Berlin Heidelberg.


The surgical therapy of pelvic floor insufficiency is mainly focused on two functional disorders, outlet obstruction and fecal incontinence. Surgery becomes of special significance after ineffectiveness of conservative treatment options. The indications for surgical interventions should be based on a precise preoperative evaluation. The dimension of functional impairment will be primarily assessed by an accurate anamnesis, application of disease-specific scoring systems and the clinical proctological basic examination that includes digital rectal examination and proctoscopy/rectoscopy. Imaging procedures (anorectal endosonography and dynamic defecography) are carried out as adjuncts and contribute to a visualization of morphological changes. Severity and manifestation of morphological symptoms are essential for the therapeutic algorithm due to increasingly differentiated surgical strategies. Only a thorough diagnostic investigation and patient selection enable a targeted therapy of obstruction and fecal incontinence. © 2012 Springer-Verlag Berlin Heidelberg.


HPV infections in the anogenital region may have very heterogeneous clinical features. Most often typical papillomatous condylomata acuminata are observed that usually present no differential diagnostic difficulty. In contrast, the clinical findings of higher grade intraepithelial dysplasias with flat papules and erythematous/ eczematous lesions are often quite inconspicuous and hardly characteristic. The goal of therapy is to prevent further progression to carcinoma, removal of bothersome tumors and avoidance of complications. Surgical methods are preferentially employed for extensive lesions, unfavorable locations and higher grade dysplasia. Options include removal with scissors or scalpel, laser therapy and electrocautery. For purely intraepithelial alterations, superficial ablative techniques are usually preferable over excision. Further developments such as argon plasma coagulation reduce the risk of unwanted deep thermal destruction with the accompanying complications. The risks for the surgeon and the surgical team during treatment should also not be neglected. With consideration of all relevant aspects, the combination of different methods may reduce the risk of complications and frequency of recurrences. Due to the high recurrence rate independent of the selected therapy, consistent follow-up after primary therapy is crucial for the long-term success. © 2010 Springer-Verlag.


Klebe S.,Universitatsklinik Wurzburg
Journal fur Neurologie, Neurochirurgie und Psychiatrie | Year: 2014

Secondary Parkinsonism (sPD) is an important differential diagnosis of idiopathic Parkinson's disease. Clinical differences between sPD and iPD may comprise (1) a sudden onset of extrapyramidal symptoms, (2) the body symmetry of symptoms, (3) low or no clinical response to dopaminergic drugs, (4) the absence of non-motor PD symptoms, (5) the presence of associated symptoms other than the characteristic key features, and (6) a normal SPECT of the dopamine transporter. Vascular Parkinsonism (vPD), drug-induced Parkinsonism (dPD), and toxic Parkinsonism (tPS) may be the most frequent etiologies but good epidemiologic data is lacking. In vPD, lesions in the watershed areas and the white matter often lead to progressive symptoms whereas strategic lesions in the basal ganglia may cause a more rapid onset. Drugs with the risk to induce Parkinsonian side effects (dPD) include antidopaminergic antipsychotics but even atypical antipsychotics are of substantial risk. Toxic Parkinsonism may be caused by carbon monoxide and heavy metal intoxication like the exposure to Manganese, eg as a by-product of the designer drug, ephedrone. Another very heterogeneous group of sPD is described by means of the term "scans without evidence of dopaminergic deficit" (SWEDD) with a normal SPECT of the dopamine transporter. SWEDDs often consist of non-neurodegenerative diseases such as dopamine-responsive dystonia, dystonic tremor, depression, vPD, or essential tremor. Therefore, SPECT of the dopamine transporter may sometimes help in the differential diagnosis of sPD. Other etiologies of sPD are inflammation, normal-pressure hydrocephalus, (recurrent) traumatic brain injury, or rare genetic disorders.


Weiss J.,Universitatsklinik Wurzburg | Rau M.,Universitatsklinik Wurzburg | Geier A.,Universitatsklinik Wurzburg
Deutsches Arzteblatt International | Year: 2014

Background: The global obesity epidemic has increased the prevalence of fatty liver disease. At present, 14% to 27% of the general population in the industrialized world has non-alcoholic fatty liver disease (NAFLD). Methods: We review pertinent publications retrieved by a selective search of the PubMed database for the years 1995 to 2013. Results: The term "non-alcoholic fatty liver disease" covers cases of a wide spectrum of severity, ranging from bland fatty liver without any inflammation and with little or no tendency to progress all the way to non-alcoholic steato - hepatitis (NASH) with inflammatory reactions and hepatocyte damage, with or without fibrosis. Some 5% to 20% of patients with NAFLD develop NASH, which undergoes a further transition to higher-grade fibrosis in 10% to 20% of cases. In fewer than 5% of cases, fibrosis progresses to cirrhosis. These approximate figures lead to an estimate of 0.05% to 0.3% for the prevalence of cirrhosis in the general population. About 2% of all cirrhosis patients per year develop hepatocellular carcinoma. The diagnosis of fatty liver disease can be suspected initially on the basis of abnormally high aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) levels and abnormal ultrasonographic findings. The positive predictive value of an ultrasonographic study for mild steatosis is 67% at most. The NAFLD fibrosis score, which is computed on the basis of multiple parameters (age, body-mass index, diabetes status, ASAT, ALAT, platelet count, and albumin level), has a positive predictive value of 82% to 90% and a negative predictive value of 88% to 93%. Liver biopsy is the gold standard for diagnosis but should be performed sparingly in view of its rare but sometimes life-threatening complications, such as hemorrhage. The treatment of NAFLD and NASH consists mainly of changes in lifestyle and nutrition. Conclusion: NAFLD can, in principle, be reversed. This is only possible with weight reduction by at least 3% to 5%.


Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy due to their capacity to present tumour antigens to effector cells. We generated cytokine-induced killer (CIK) cells from healthy donors and examined their responses in vitro in an LDH release assay against three cell lines and allogeneic HLA non-matched blasts from three patients with de novo AML after coincubation with autologous peripheral blood monocyte-derived DCs. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the patients' AML cells increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced or even reversed the cytotoxic activity of the effector cells. This decrease of allogeneic cytotoxicity led us to conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable. ©2011 Schöttker et al.


Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy due to their capacity to present tumour antigens to effector cells. We generated cytokine-induced killer (CIK) cells from healthy donors and examined their responses in vitro in an LDH release assay against three cell lines and allogeneic HLA non-matched blasts from three patients with de novo AML after coincubation with autologous peripheral blood monocyte-derived DCs. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the patients' AML cells increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced or even reversed the cytotoxic activity of the effector cells. This decrease of allogeneic cytotoxicity led us to conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable.

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