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Wahlgren N.,Karolinska Institutet | Wahlgren N.,Karolinska University Hospital | Moreira T.,Karolinska Institutet | Moreira T.,Karolinska University Hospital | And 25 more authors.
International Journal of Stroke | Year: 2016

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN). © 2016 World Stroke Organization.

Zimbelmann M.,UKSH | Cordes J.,University of Lübeck
Phlebologie | Year: 2015

There are no cases reported about endovascular varicosis therapy having an impact on the erectile function of the man. This case reports' patient had a stronger erection in the area of the glans penis after he underwent endovenous lasertherapy of the great saphenous vein. This effect could also be explained with the anatomy of the veins because some of the blood of the penis is drained by the external pudendal vein which leads into the saphenofemoral junction. If there is a manipulation on the veins of the saphenofemoral junction it might have an impact on the drainage of the penis. © Schattauer 2015.

Dunst J.,University of Lübeck | Rades D.,UKSH
Onkologe | Year: 2014

Background. This review article summarizes the contemporary standard of fractionated external beam radiation therapy in the management of brain metastases. Material and methods. The results of meta-analyses, randomized studies and prospective cohort studies were analyzed with emphasis on the role of whole-brain irradiation (WBI). Results. For patients with 1-3 brain metastases, local therapy (radiosurgery or resection) is the treatment of choice. Additional WBI improves intracranial control without impacting on overall survival (level of evidence LoE I). The highest risk of recurrence is after resection of metastases without additional radiotherapy and adjuvant local radiotherapy of the resection cavity has demonstrated high local control rates (LoE II). For patients with multiple (more than three) metastases WBI is the only modality with a proven impact on survival (LoE I). For patients with a very poor prognosis, short-term radiotherapy regimens are recommended and additional systemic therapy does not improve survival (LoE I). Protection of brain function with modern radiotherapy techniques (sparing of the hippocampus) seems to be feasible and effective and is currently under investigation. Conclusions. For patients with multiple brain metastases (n ≥ 4) fractionated WBI remains the standard of care. © 2014 Springer-Verlag Berlin Heidelberg.

Ungefroren H.,Clinic for Applied Cellular Medicine | Sebens S.,University of Kiel | Sebens S.,Laboratory of Molecular Gastroenterology and Hepatology | Groth S.,Clinic for Applied Cellular Medicine | And 2 more authors.
Current Cancer Drug Targets | Year: 2011

Both the nonreceptor tyrosine kinase Src and the receptors for transforming growth factor (TGF)-β (TβRI, TβRII) play major roles during tumorigenesis by regulating cell growth, migration/invasion and metastasis. The common Src family kinase inhibitors PP2 and PP1 effectively block Src activity in vitro and in vivo, however, they may exert nonspecific effects on other kinases. In this study, we have evaluated PP2 and PP1 for their ability to inhibit TGFβ1-mediated responses in the TGF-β-responsive pancreatic adenocarcinoma cell line Panc1. We show that PP2 and PP1 but not the more specific Src inhibitor SU6656 effectively relieved TGF-β1-induced growth arrest and p21WAF1 induction, while basal growth was enhanced by PP2 and PP1, and suppressed by SU6656. PP2 and PP1 but not SU6656 also suppressed TGF-β1-induced epithelial-to-mesenchymal transition (EMT) as evidenced by their ability to inhibit downregulation of the epithelial marker E-cadherin, and upregulation of the EMT-associated transcription factor Slug. Likewise, PP2 and PP1 but not SU6656 effectively blocked TGF-β1-induced activation of Smad2 and p38 MAPK and partially suppressed Smad activation and transcriptional activity on TGF-β/Smad-responsive reporters of a kinase-active TβRI mutant ectopically expressed in Panc1 cells. Interestingly, PP2 and PP1 strongly inhibited recombinant TβRI in an in vitro kinase assay, with PP1 being more potent and PP2 being nearly as potent as the established TβRI inhibitor SB431542. PP2 but not PP1 also weakly inhibited the TβRII kinase. Together, these data provide evidence that PP2 and PP1 are powerful inhibitors of TβR function that can block TGF-β/Smad signaling in a Src-unrelated fashion. Both agents may be useful as dual TGF-β/Src inhibitors in experimental therapeutics of late stage metastatic disease. © 2011 Bentham Science Publishers Ltd.

Hefti M.,UKSH | Campe G.V.,Universittslinik Graz | Schneider C.,Kantonsspital Winterthur | Roelcke U.,Kantonsspital Aarau
Zentralblatt fur Neurochirurgie | Year: 2010

Objective: Improvements in microneurosurgical techniques, radiotherapy and chemotherapy for the treatment of high grade gliomas resulted in better local tumor control and longer progression-free survival. Multicentric (MC) lesions located distant from the initial resection area contribute to treatment failure in a growing number of patients. These MC lesions may develop within the course of the disease (metachronous) or may already be present at the time of first tumor manifestation (synchronous). To look for mechanisms and regular patterns behind MC glioma manifestations and to investigate whether they are a second primary tumor or the result of continuous diffuse glioblastoma cell invasion, we retrospectively analyzed the initial and all follow-up MR studies of our high grade glioma (HGG) patients. Patients and Methods: MR studies of 247 consecutive patients treated for HGG at a single institution were analyzed. MC tumor manifestation was defined as more than one gadolinium enhancing lesion within the brain on MRI without a connecting signal alteration in T2 sequences and/or without a connecting hypointense mass in T1 sequences. The minimal distance to define two solitary lesions was set at >10mm. According to these specifications 40 patients showed MC tumor manifestations in their MR studies on admission or during treatment of their disease. The MR studies of these cases were retrospectively analyzed for patterns in MC tumor manifestation and progression. Topographical specifications and delay in manifestation were used to explain possible pathways of development. Kaplan Meyer survival graphs for metachronous and synchronous MC disease were calculated. Results: 24 patients showed MC tumor manifestation at the time of admission. 16 cases developed MC manifestation within a follow-up period of 357 months. The location of all lesions could be categorized into one of three distinct patterns (white matter, subependymal, intraventricular). The patterns showed individual and location-specific time gaps to metachronous manifestation. Calculated from the time of first tumor diagnosis, the median survival was longer for patients with metachronous MC lesions (353 days, p<0.05) compared to patients with synchronous MC lesions (110 days) or patients without multicentricity (234 days). Patients with metachronous lesions showed a similar survival (72 days) as patients with synchronous MC lesions (110 days) once they developed MC disease. Conclusion: The topographical patterns and temporal characteristics of MC disease suggest that all manifestations share common mechanisms such as an active migratory process. Our data therefore do not support the concept of an independent MC development of multiple gliomas. © Georg Thieme Verlag KG Stuttgart New York.

In the last years, the Danish debate about priority setting in medicine has gained new strength. This paper shows the main focuses of the current discussion based on a research of Danish primary literature. For the first time since the 1990s the Danish Council of Ethics has been involved with priority setting in medicine in a project running from 2011 to 2013. The Council emphasises the importance of legitimate processes and calls for visible values and criteria. A focus of the debate is how to deal with new expensive drugs. Politicians, physicians, health economists and the Council of Ethics have called for a national institution for priority setting in medicine. They have mainly looked to the Norwegian National Council for Priority Setting in Health Care and the British National Institute for Health and Care Excellence for inspiration. The Danish Government considered establishing a national institute for priority setting, but the plans were not put into practice. In the year 2012 a new national project was launched to create clinical guidelines. Danish doctors welcome the guidelines as a good basis for priority setting. Just like in earlier Danish priority setting debates, a coordinating institution is lacking to bundle the discussion and keep it going. The debate seems to have come to an end once again. The fact that it was seriously considered to establish an institute for priority setting is a new development. It can be expected that the discussion will be resumed in the near future, possibly the idea of an institute for priority setting will be readopted. The general conditions for priority setting in health care have improved. © Georg Thieme Verlag KG Stuttgart, New York.

Holle J.U.,UKSH | Reinhold-Keller E.,Die Rheuma Spezialisten | Gross W.L.,UKSH
Zeitschrift fur Rheumatologie | Year: 2012

Granulomatosis with polyangitis (GPA, Wegener's granulomatosis) is characterized by a granulomatous inflammation of the respiratory tract and a necrotizing ANCA-associated small to medium-size vessel vasculitis with a predilection for the lungs (pulmonary capillaritis) and kidneys (necrotizing glomerulonephritis). The disease evolves stage-wise and typically starts as inflammation of the respiratory tract followed by development of systemic vasculitis manifestations. Today, treatment is evidence-based and adapted according to activity and disease stage which has resulted in a significant improvement in long-term outcome. Early mortality during the first year of treatment poses one of the main problems and is a result of infections under immunosuppressive treatment. Furthermore, treatment of refractory disease activity which is often represented by granulomatous manifestations is still a challenge and may result in significant organ damage if not treated successfully. © 2012 Springer-Verlag Berlin Heidelberg.

Ungefroren H.,Clinic for Applied Cellular Medicine | Sebens S.,University of Kiel | Sebens S.,C o Laboratory of Molecular Gastroenterology and Hepatology | Groth S.,Clinic for Applied Cellular Medicine | And 2 more authors.
International Journal of Oncology | Year: 2011

Both transforming growth factor (TGF)-β and the non-receptor tyrosine kinase Src play major roles during tumorigenesis by regulating cell growth, epithelial-to-mesenchymal transition (EMT), migration/invasion and metastasis, but little is known about the signaling crosstalk between them. To interfere with Src function in vitro and in vivo many studies have employed the pharmacologic Src inhibitors PP2 and PP1. Both agents have recently been shown to be powerful inhibitors of TGF-β receptor type I/ALK5 and type II. As this situation prohibited any definite conclusions with respect to the relative contribution of TGF-β vs. Src signaling, we decided to reappraise a potential role of Src in TGF-β1-mediated cellular responses using RNA and dominant-negative (dn) interference to block Src expression and function, respectively. In TGF-β-responsive pancreatic ductal adenocarcinoma (PDAC) cells, we show that Src is activated by TGF-β1 and that its specific inhibition strongly attenuated basal proliferation and enhanced TGF-β1-mediated growth arrest. However, Src inhibition was unable to impair TGF-β1-controlled EMT as evidenced by cell morphology and regulation of the epithelial marker E-cadherin. Despite its dispensibility for TGF-β-induced EMT, specific inhibition of Src dramatically reduced basal and TGF-β1-induced cell migration in Panc-1 cells as measured with a novel real-time migration assay (xCELLigence DP system). Biochemically, dnSrc inhibition failed to block TGF-β1/ALK5-induced activation of Smad2 and Smad3, but partially inhibited transcriptional activation of TGF-β/Smad-responsive reporter genes, and effectively blocked basal and TGF-β1-induced activation of p38 MAPK. Together, the data provide evidence for a role of Src in the regulation of basal proliferation as well as in basal and TGFβ1-mediated cell motility but not EMT in TGF-β-responsive pancreatic (tumor) cells.

Bartscht T.,UKSH | Lehnert H.,UKSH | Gieseler F.,UKSH | Ungefroren H.,UKSH
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose We have previously demonstrated that in pancreatic ductal adenocarcinoma (PDAC)-derived cell lines, the common Src family kinase inhibitors PP2 and PP1 effectively inhibited morphologic alterations associated with TGFβ1-mediated epithelial-to-mesenchymal transition (EMT) by blocking the kinase activity of the TGF-β type I receptor ALK5 rather than Src (Ungefroren et al. in Curr Cancer Drug Targets 11:524, 2011). In this report, the ability of PP2 and PP1, the more specific Src inhibitor SU6656, and the ALK5 inhibitor SB431542 to functionally block TGF-β1-dependent EMT and cell motility in established PDAC (Panc-1, Colo 357) and primary NSCLC (Tu459) cell lines were investigated. Methods The effects of PP2, PP1, SU6656, and SB431542 on TGF-β1-dependent cell scattering/EMT, cell migration/invasion, and expression of invasion-associated genes were measured by using the real-time cell analysis assay on the xCELLigence system and quantitative realtime RT-PCR, respectively. Results In all three cell lines tested, PP1, PP2, and SB431542 effectively blocked TGF-β1-induced cell scattering/ EMT, migration, and invasion and in Colo 357 cells inhibited the induction of the invasion-associated MMP2 and MMP9 genes. In contrast, SU6656 only blocked TGFβ1- induced invasion in Panc-1 and Tu459 but not Colo 357 cells. PP1, and to a greater extent PP2, also inhibited the high spontaneous migratory activity of Panc-1 cells expressing a kinase-active ALK5 mutant. Conclusions These data provide evidence that PP2 and PP1 are powerful inhibitors of TGF-β-induced cell migration and invasion in vitro and directly target ALK5. Both agents may be useful as dual TGF-β/Src inhibitors in experimental therapeutics to prevent metastatic spread in late-stage PDAC and NSCLC. © Springer-Verlag 2012.

PubMed | UKSH
Type: | Journal: Anti-cancer agents in medicinal chemistry | Year: 2017

In a series of studies carried out over the last couple of years in various cell types, it was observed that the experimentally used Src family kinase inhibitors PP1 and PP2 and the clinically used Src/Abl inhibitors AZM475271 and dasatinib are potent inhibitors of TGF- mediated cellular responses such as Smad and p38 mitogen-activated protein kinase phosphorylation, Smad-dependent transcriptional activation, growth inhibition, epithelial-mesenchymal transition (EMT), and cell motility. While for PP1/PP2 it was demonstrated shown that these agents directly inhibit the kinase activity of the TGF- type I receptor activin receptor-like kinase 5, the mechanism of the anti-TGF- effect of AZM475271 and dasatinib is less clear. In contrast, the anti-TGF- effect of yet another Src/Abl inhibitor, bosutinib, is more variable with respect to the type of the TGF- response and the cell type affected, and lacks a clear dose-dependency. In the light of their strong anti-activin receptor-like kinase 5 kinase effect, PP1 and PP2 should not be used when studying the role of c-Src as downstream mediators in TGF-/activin receptor-like kinase 5 signaling. On the other hand, based upon in vitro findings, it is conceivable that part of the therapeutic effects of AZM475271 and dasatinib seen in preclinical and clinical studies with solid tumors was caused by inhibition of prometastatic TGF- rather than Src signaling. If AZM475271 and dasatinib can indeed act as dual Src / TGF- inhibitors in vivo, this may be beneficial for prevention of metastatic disease in more advanced tumor stages.

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