Kruis W.,Evangelisches Krankenhaus Kalk |
Germer C.-T.,Universitatsklinikum Wurzburg |
Leifeld L.,Medizinische Klinik 3 Gastroenterologie und Allgemeine Innere Medizin
Digestion | Year: 2014
Background: Diverticular disease is one of the most common disorders of the gastrointestinal tract. 28-45% of the population develop colonic diverticula, while about 25% suffer symptoms and about 5% complications. Aim: To create formal guidelines for diagnosis and management. Methods: Six working groups with 44 participants analyzed key questions in subject areas assigned to them. Following a systematic literature search, 451 publications were included. Consensus was obtained by agreement within the working groups, two Delphi processes and a guideline conference. Results: Targeted management of diverticular disease requires a classificatory diagnosis. A new classification was created. In addition to the clinical examination, intestinal ultrasound or computed tomography is the determining factor. Interval colonoscopy is recommended to exclude comorbidities. A low-fiber diet, obesity, lack of exercise, smoking and immunosuppression have an adverse impact on diverticulosis. This can lead to diverticulitis. Antibiotics are no longer recommended in uncomplicated diverticulitis if no risk factors such as immunosuppression are present. If close monitoring is ensured, uncomplicated diverticulitis can be treated on an outpatient basis. Complicated diverticulitis should be treated in hospital, involving broad-spectrum antibiotic therapy, where necessary abscess drainage, and surgery, if possible laparoscopically. In the case of chronic relapsing diverticulitis, the risk of perforation decreases with each episode, so that surgery is no longer recommended after the second episode but only following individual assessment. Conclusions: New findings on diverticular disease call into question the overuse of antibiotics and excessive indications for surgery. Targeted treatment requires a precise diagnosis and intensive interdisciplinary cooperation. © 2014 S. Karger AG, Basel.
Volkmann J.,Universitatsklinikum Schleswig Holstein |
Daniels C.,Universitatsklinikum Wurzburg |
Witt K.,Universitatsklinikum Schleswig Holstein
Nature Reviews Neurology | Year: 2010
Neurostimulation of the subthalamic nucleus (STN) is an established treatment for motor symptoms in advanced Parkinson disease (PD), although concerns exist regarding the safety of this therapy in terms of cognitive and psychiatric adverse effects. The basal ganglia are considered to be part of distributed cortico-subcortical networks that are involved in the selection, facilitation and inhibition of movements, emotions, behaviors and thoughts. The STN has a central role in these networks, probably providing a global 'no-go' signal. The behavioral and cognitive effects observed following STN high-frequency stimulation (HFS) probably reflect the intrinsic role of this nucleus in nonmotor functional domains. Nevertheless, postoperative behavioral changes are seldom caused by such stimulation alone. PD is a progressive neurodegenerative disorder with motor, cognitive, behavioral and autonomic symptoms. The pattern of neurodegeneration and expression of these symptoms are highly variable across individuals. The preoperative neuropsychiatric state can be further complicated by sensitization phenomena resulting from long-term dopaminergic treatment, which include impulse control disorders, punding, and addictive behaviors (dopamine dysregulation syndrome). Finally, personality traits, the social environment, culture and learned behaviors might be important determinants explaining why behavioral symptoms differ between patients after surgery. Here, we summarize the neuropsychiatric changes observed after STN HFS and try to disentangle their various etiologies. © 2010 Macmillan Publishers Limited. All rights reserved.
Rollig C.,TU Dresden |
Knop S.,Universitatsklinikum Wurzburg |
Bornhauser M.,TU Dresden
The Lancet | Year: 2015
Summary Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future. © 2015 Elsevier Ltd.
Von Rahden B.H.A.,University of Würzburg |
Von Rahden B.H.A.,Universitatsklinikum Wurzburg |
Germer C.-T.,University of Würzburg
Langenbeck's Archives of Surgery | Year: 2012
Purpose: This paper aims to review the current evidence regarding pathogenesis of colonic diverticular disease and its complications, which are a major health problem in the Western world. Methods: Based on selective Medline searches, relevant literature was indentified regarding pathogenesis of (1) diverticulosis/ formation of diverticula, (2) diverticulitis/inflammation of diverticula, (3) complicated diverticulitis/perforation, and (4) diverticular bleeding. Results: Pathogenesis of colonic diverticula is regarded as a multifactorial process, involving dietary factors (Western low-fiber diet), structural changes of the colonic wall (altered musculature, collagen, elastin, etc.) and functional changes (motility disorder, increased intraluminal pressure). Genetic changes are also discussed and aging is also a key factor. Pathogenesis of inflammation (diverticulosis) is regarded as a result of microperforations at the fundus of the diverticulum, and not an abscessed diverticulum due to an impacted fecolith. Histamine and its receptors do also seem to play a role, corresponding with the promising prophylactic approach with probiotics. Pathogenesis of complicated diverticulitis is characterized by perforation, which is the cardinal feature. Furthermore, an intensive inflammatory infiltrate with macrophages is found in surgical specimens, even after antibiotic pretreatment. Steroid intake and immunosuppression are risk factors and only recently a glucocorticoid-induced tumor necrosis factor-receptor has been suggested to resemble the molecular link. Diverticular bleeding is a distinct disease process - which does usually take place without diverticulitis - and is due to eccentric rupture of the vas rectum. Conclusions: The pathophysiology of diverticular disease is multifactorial. Some of the current evidence has important implications for clinical practice, e.g., the suggested role of steroid intake and immunosuppression for complicated diverticulitis. © Springer-Verlag 2012.
Brack A.,Universitatsklinikum Wurzburg |
Rittner H.L.,Universitatsklinikum Wurzburg |
Stein C.,Free University of Berlin
Journal of Neuroimmune Pharmacology | Year: 2011
Opioid-induced immunosuppression has been demonstrated in cell culture experiments and in animal models. This is in striking contrast to the paucity of confirmatory studies in humans. This review describes the basic pharmacokinetics and -dynamics of opioid use in patients. It summarizes the major findings on opioid use and infectious complications in intensive care unit (ICU) patients, in patients with acute or chronic non-malignant pain, and in intravenous drug users (IDU). The limitations of studies in each area are discussed. For example, ethical concerns may complicate randomized placebo-controlled trials (RCT) in acute postoperative pain and for a large part of ICU patients. Importantly, most studies in patients with chronic (non-malignant) pain only inadequately report infectious complications in relation to opioid use since their incidence is usually not considered to be drug related. Infectious complications in IDUs are very frequent but cannot easily be distinguished from risk behavior or risk environment. In summary, convincing clinical evidence is lacking that opioids per se increase the rate of infectious complications in most patient categories. From a clinical standpoint, important unresolved issues are i) selection of relevant animal models, ii) opioid selection and discontinuation, and iii) the role of coexisting diseases and concomitant other medications. © 2011 Springer Science+Business Media, LLC.
Vorlova S.,Universitatsklinikum Wurzburg
Oncogene | Year: 2016
The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor’s vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.Oncogene advance online publication, 6 June 2016; doi:10.1038/onc.2016.182. © 2016 Macmillan Publishers Limited
Guckenberger M.,Universitatsklinikum Wurzburg |
Lawrenz I.,Universitatsklinikum Wurzburg |
Flentje M.,Universitatsklinikum Wurzburg
Strahlentherapie und Onkologie | Year: 2014
Purpose: To evaluate long-term outcome after dose-escalated, moderately hypofractionated radiotherapy for prostate cancer. Methods: Since 2005, 150 consecutive patients were treated with primary radiotherapy for localized prostate cancer. Intensity modulated radiotherapy (IMRT) using the simultaneous integrated boost (SIB) technique was practiced in all patients and doses of 73.9 Gy (n = 41) and 76.2 Gy (n = 109) were delivered in 32 and 33 fractions, respectively. The pelvic lymph nodes were treated in 41 high-risk patients. Treatment was delivered using cone-beam CT based image-guided radiotherapy (IGRT). Toxicity was assessed prospectively using CTCAE 3.0; biochemical failure was defined according to the Phoenix definition of nadir + 2 ng/ml. Results: Median follow-up of living patients was 50 months. Gastrointestinal (GI) toxicity was mild with > 80 % of the patients free from any GI toxicity during follow-up and no time trend to increased rates or to higher grade of GI toxicity. Two patients suffered from late grade 3 GI toxicity. Acute genitourinary (GU) toxicity grade 1-2 was observed in 85 % of the patients; most patients recovered quickly within 6 weeks after treatment. The rate of GU toxicity grade ≥ 2 was < 10 % at 6-12 month but increased continuously to 22.4 % at 60 months; grade 3 GU toxicity remained below 5 % during follow-up. The 5-year freedom from biochemical failure (FFBF) was 82 % for all patients and 88, 80, and 78 % for low-, intermediate-, and high-risk disease. Conclusion: Favorable FFBF with simultaneously low rates of toxicity was observed after moderately hypofractionated radiotherapy with 2 Gy-equivalent doses ≥ 80 Gy. Conformal IMRT planning and accurate IGRT treatment delivery may have contributed to these results. © 2013 Springer Heidelberg Berlin.
Monjezi R.,Universitatsklinikum Wurzburg
Leukemia | Year: 2016
Immunotherapy with T cell modified with gamma-retroviral or lentiviral (LV) vectors to express a chimeric antigen receptor (CAR) has shown remarkable efficacy in clinical trials. However, the potential for insertional mutagenesis and genotoxicity of viral vectors is a safety concern, and their cost and regulatory demands a roadblock for rapid and broad clinical translation. Here, we demonstrate that CAR T cells can be engineered through non-viral Sleeping Beauty (SB) transposition of CAR genes from minimalistic DNA vectors called minicircles (MCs). We analyzed genomic distribution of SB and LV integrations and show that a significantly higher proportion of MC-derived CAR transposons compared with LV integrants had occurred outside of highly expressed and cancer-related genes into genomic safe harbor loci that are not expected to cause mutagenesis or genotoxicity. CD19-CAR T cells engineered with our enhanced SB approach conferred potent reactivity in vitro and eradicated lymphoma in a xenograft model in vivo. Intriguingly, electroporation of SB MCs is substantially more effective and less toxic compared with conventional plasmids, and enables cost-effective rapid preparation of therapeutic CAR T-cell doses. This approach sets a new standard in advanced cellular and gene therapy and will accelerate and increase the availability of CAR T-cell therapy to treat hematologic malignancies.Leukemia advance online publication, 5 August 2016; doi:10.1038/leu.2016.180. © 2016 Macmillan Publishers Limited, part of Springer Nature.
Zernecke A.,Universitatsklinikum Wurzburg
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015
Atherosclerotic vascular disease is driven by chronic inflammation involving both innate and adaptive immune responses. Dendritic cells (DCs) are found in healthy arteries and accumulate in atherosclerotic lesions and engage in diverse pathogenic and protective mechanisms during atherogenesis. DCs contribute to early foam cell formation, regulate lipid metabolism, and control pro- and antiatherosclerotic T-cell responses by multifarious mechanisms. We, here, review the roles of DCs and plasmacytoid DCs in experimental models of atherosclerosis and the approaches to target DCs in therapeutic vaccination strategies. We, furthermore, discuss the evidence of the potential function of DCs in human atherosclerosis, and dissect the efforts to harness DC subsets as biomarkers of disease. Finally, we discuss necessary future steps that will help to understand the specific contribution of bona fide DCs in atherosclerosis to move toward novel therapeutic approaches. © 2015 American Heart Association, Inc.
Bluemel C.,Universitatsklinikum Wurzburg
Clinical nuclear medicine | Year: 2013
Diagnosis of ectopic Cushing syndrome is challenging. The best imaging approach for localizing ectopic ACTH-secreting tumors is not defined. Here, we report on a 68-year-old woman with new-onset hypertension (>200/90 mm Hg) who was referred to our institution with suspicion of ectopic ACTH-secreting tumor for further work-up. Combined FDG PET/CT as a whole-body imaging modality revealed a neuroendocrine tumor of the pancreatic tail confirmed by surgical exploration.