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Recombinant porcine factor VIII (rpFVIII, OBI-1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA). Inhibitors in AHA can sometimes cross-react with rpFVIII.To assess the frequency, strength, and determinants of cross-reactivity.Baseline samples from 70 patients of the prospective, observational cohort study GTH-AH 01/2010 were assessed for anti-human FVIII and anti-rpFVIII inhibitors using modified Nijmegen-Bethesda assays, as well as anti-human FVIII domain reactivity using enzyme-linked immunoassay (ELISA).Anti-human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti-rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti-rpFVIII titers were ≤5 BU in most patients. Patients with cross-reacting inhibitors, as compared to patients without, had significantly higher anti-human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (1 versus 2.6 IU/dL). The ratio between anti-rpFVIII to anti-human titers was highest for inhibitors involving the C1 domain. Cross-reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti-human FVIII titer of100 BU/mL predicted cross-reactivity with 97% likelihood, whereas an anti-human FVIII titer of3.8 BU/mL predicted absent cross-reactivity with 90% likelihood.Cross-reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross-reactivity is frequent in patients with anti-human FVIII titers of100 BU/mL.

Background A dysregulated glucose metabolism in synovial fibroblasts (SF) has been associated with their aggressive phenotype in rheumatoid arthritis (RA). Even though T helper (Th) cells are key effector cells in the propagation and exacerbation of synovitis in RA, little is known about their influence on the metabolism of SF. Thus, this study investigates the effect of Th cells on the glucose metabolism and phenotype of SF and how this is influenced by the blockade of cytokines, janus kinases (JAKs) and glycolysis. Methods SF from patients with RA or osteoarthritis (OA) were cultured in the presence of a stable glucose isotopomer ([U-13C]-glucose) and stimulated with the conditioned media of activated Th cells (ThCM). Glucose consumption and lactate production were measured by proton nuclear magnetic resonance (1H NMR) spectroscopy. Cytokine secretion was quantified by ELISA. The expression of glycolytic enzymes was analysed by PCR, western blot and immunofluorescence. JAKs were blocked using either baricitinib or tofacitinib and glycolysis by using either 3-bromopyruvate or FX11. Results Quiescent RASF produced significantly higher levels of lactate, interleukin (IL)-6 and matrix metalloproteinase (MMP) 3 than OASF. Stimulation by ThCM clearly changed the metabolic profile of both RASF and OASF by inducing a shift towards aerobic glycolysis with strongly increased lactate production together with a rise in IL-6 and MMP3 secretion. Interestingly, chronic stimulation of OASF by ThCM triggered an inflammatory phenotype with significantly increased glycolytic activity compared to unstimulated, singly stimulated or re-stimulated OASF. Finally, in contrast to cytokine-neutralizing biologics, inhibition of JAKs or glycolytic enzymes both significantly reduced lactate production and cytokine secretion by Th cell-stimulated SF. Conclusions Soluble mediators released by Th cells drive SF towards a glycolytic and pro-inflammatory phenotype. Targeting of JAKs or glycolytic enzymes both potently modulate SF’s glucose metabolism and decrease the release of IL-6 and MMP3. Thus, manipulation of glycolytic pathways could represent a new therapeutic strategy to decrease the pro-inflammatory phenotype of SF.

Background The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups. Methods The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016. Results Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact. Conclusions Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.

Background: There is growing evidence for a dysregulated glucose metabolism of synovial fibroblasts (SF) in rheumatoid arthritis (RA) being a prerequisite for their aggressive phenotype. As yet, little is known about the influence of immune cells on the metabolism of SF although local infiltration of[for full text, please go to the a.m. URL], 46. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 32. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), Wissenschaftliche Herbsttagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA.

Die neue Forschungs-Kernbohrung aus Heidelberg wird beschrieben und gegliedert. Die Forschungs- und Bohraktivitäten im Heidelberger Becken (HDB) begannen im Jahr 2002; sie erschließen ein kontinentales Sedimentarchiv im Oberrheingraben (URG). Im HDB wird eine der längsten Sedimentabfolgen quartärer Sedimente in Europa erwartet, dank kontinuierlicher Subsidenz des Beckens in Verbindung mit kontinuierlichem Input von Sedimenten unterschiedlicher Herkunft. Das HDB befindet sich auf halber Strecke zwischen dem alpinen Einzugsgebiet des Rheins und seiner Mündung in die Nordsee. Eine kontinuierliche Sedimentation ist hier eher möglich als am Alpenrand mit seinen Schmelzwasser-Erosionsereignissen oder an der Küste mit ihren Meeresspiegelschwankungen. Dieser eher geringe Einfluss des Klimas hat zur Folge, dass die Tektonik eine umso größere Rolle bei der Steuerung der Sedimentation spielt. Die über 500 m mächtige quartäre Abfolge ist daher in erster Linie durch Tektonik kontrolliert, wobei Klimasignale ebenfalls erkannt werden können. Die hier vorgestellte Gliederung der Abfolge beruht auf Provenienz, Lithofazies und wechselnden Verhältnissen von Akkomodationsraum und Sedimentinput (a/s-ratio). Dazu kommen biostratigraphische Zeitmarken. Im skizzierten Sedimentations-Szenario dominieren fluviale Verhältnisse; dazwischen zwei lakustrine Abschnitte. Letztere sind verknüpft mit zunehmendem Akkomodationsraum, der in mindestens einer Zeitscheibe über die Grabenrandstörung hinweg sich bis in die Täler des Odenwalds erstreckt., research

Im Sommer 2014 hat die European Society of Cardiology die uberarbeitete Leitlinie zur Behandlung der akuten Lungenembolie herausgegeben. Dieser Artikel stellt die wichtigsten Empfehlungen daraus zur Behandlung der haufig vital bedrohten Patienten auf der Intensivstation vor.

Als Komplikation einer provozierten (z.B. nach orthopadischer Operation) oder unprovozierten (ohne erkennbaren Ausloser) tiefen Venenthrombose droht der Tod durch eine Lungenembolie. Eine Lungenembolie kann einerseits wahrend der Behandlung kritisch kranker Patienten auf der Intensivstation entstehen, andererseits werden akut an einer Lungenembolie erkrankte Patienten haufig primar auf einer Intensivstation behandelt. Daher muss jeder auf einer Intensivstation tatige Arzt mit Pathogenese, Diagnostik und Therapie der Lungenembolie vertraut sein. Im Sommer 2014 hat die European Society of Cardiology (ESC) eine exzellent ausgearbeitete und im Klinikalltag sehr hilfreiche Leitlinie herausgegeben, deren wichtigste Punkte und insbesondere fur die Akuttherapie relevante Empfehlungen im Folgenden zusammengefasst werden (Infobox 1) [1].

Ristocetin cofactor activity of Von Willebrand factor (VWF:RCo) and the ratio VWF:RCo to its antigen VWF:Ag are used as routine screening to estimate VWF function and to detect types of Von Willebrand disease (VWD) caused by loss of high molecular weight multimers. However, the VWF:RCo test is prone to analytic imprecisions due to various reasons. We compared an assay for VWF activity (VWF:Ac) with VWF:RCo putting emphasis on the ratios to VWF:Ag.We evaluated 942 samples from 432 patients and evaluated three groups in detail: normal patients (normal multimers, VWF:Ag and VWF:RCo0.5 U/ml, VWD type 1 excluded; n=258), VWD type 1 (n=76) and acquired Von Willebrand syndrome (AVWS, n=326). In addition, 30 healthy subjects were analysed.VWF:Ac and VWF:RCo correlated well (Pearson´s r=0.96, p0.01), so did their ratios to VWF:Ag (Pearson´s r=0.82, p0.01). We calculated the normal range of VWF:Ac/VWF:Ag for healthy subjects as 0.8-1.16. In comparison, the reference range (mean±2std) derived from normal patient samples was 0.73-1.14. The corresponding ranges for VWF:RCo/VWF:Ag came to 0.74-1.23 (healthy) and 0.62-1.25 (normal patients). The ratios showed similar results regarding VWD type 1. The sensitivity for AVWS was higher with VWF:Ac/VWF:Ag than with VWF:RCo/VWF:Ag (97.5% versus 84.7%).The data suggest that the results obtained with the VWF:Ac assay are comparable to that of the VWF:RCo assay. An AVWS was more reliably detected by VWF:Ac/VWF:Ag. We assume that the VWF:Ac assay could replace VWF:RCo for routine screening for AVWS, especially when prompt evaluation is required.

Objective To report a case of a patient with multiple cerebral cavernous malformations (CCM). Observation A 22 year old man with mild von Willebrand disease presented with two occipital CCM, one of them with acute hemorrhage. Genetic testing for CCM1–3 did not reveal a mutation. Over a period of 54 months, the patient suffered 26 new CCM hemorrhages despite multiple treatment attempts including thalidomide, simvastatin and hemostatic factors. Only after initiation of propranolol, which has already been successfully used in three children with giant cerebral cavernoma, the occurrence of new CCM with hemorrhages was completely stopped already at dose of 30 mg daily – now for a period of 26 months and without any other medications. Conclusion This case suggests a protective role for propranolol in preventing the occurrence of new cerebral cavernoma with hemorrhages in adults with multiple CCM.

Background: We examined whether or not extended prophylaxis with low molecular weight heparin (LMWH) would significantly reduce thromboembolic event (TEE) rates in germ cell cancer patients undergoing cisplatin-based chemotherapy. Patients and Methods: LMWH prophylaxis was given from the first day of chemotherapy until 21 days after completing the last chemotherapy cycle to 45 out of 93 (48.4%) patients (extended), and to 48 out of 93 (51.6%) patients during their hospitalization only (limited) between January 2008 and December 2013. Patients were analyzed retrospectively for TEEs such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) or peripheral arterial thrombosis. Results: A total of 22/93 (23.7%) patients experienced 30 TEE during chemotherapy: 12 out of 30 (40%) deep vein thrombosis, 4 out of 30 (13.3%) MI, 10 out of 30 (33.3%) PE and 4 out of 30 peripheral arterial thrombosis (13.3%). TEE rates in both groups did not differ significantly (extended: 26.7 vs. limited: 20.8%). Conclusions: The introduction of extended LMWH prophylaxis did not significantly reduce TEE rates in our patient cohort.

Background.Much work has been done to evaluate the outcome of integrative inpatient treatment but scarcely the costs. This paper evaluates the costs for inpatient treatment in three anthroposophic hospitals (AHs).Material and Methods.Cost and performance data from a total of 23,180 cases were analyzed and compared to national reference data. Subgroup analysis was performed between the cases with and without anthroposophic medical complex (AMC) treatment.Results.Costs and length of stay in the cases without AMC displayed no relevant differences compared to the national reference data. In contrast the inlier cases with AMC caused an average of € 1,394 more costs. However costs per diem were not higher than those in the national reference data. Hence, the delivery of AMC was associated with a prolonged length of stay. 46.6% of the cases with AMC were high outliers. Only 10.6% of the inlier cases with AMC were discharged before reaching the mean length of stay of each DRG.Discussion.Treatment in an AH is not generally associated with an increased use of resources. However, the provision of AMC leads to a prolonged length of stay and cannot be adequately reimbursed by the current G-DRG system. Due to the heterogeneity of the patient population, an additional payment should be negotiated individually.

SUMMARY Background: The diagnosis of soft-tissue sarcomas of the limbs is often delayed, sometimes markedly so, even though prompt and appropriate treatment improves survival and lowers the amputation rate. Methods: On the basis of a selective literature review and consideration of the relevant guidelines, we developed an algorithm that can serve as a guide to the diagnosis of soft-tissue tumors in general and to the treatment of softtissue sarcomas of the limbs. Results: Surgical resection accompanied by multimodal therapy is the only treatment strategy for soft-tissue sarcoma that provides a chance of cure. Particularly when the tumor is located in the distal part of a limb, plasticreconstructive surgical techniques often enable adequate local control, along with limb salvage and preservation of function. The role of adjuvant or neo-adjuvant radiotherapy and/or chemotherapy is currently debated. The overall survival rate at 5 years is 87% for low-grade sarcomas and 62% for high-grade sarcomas. Conclusion: Any solid mass of the limbs that has been present for more than four weeks requires diagnostic evaluation. Excisional biopsy is suitable only for epifascial lesions measuring less than 5 cm in diameter. All other lesions should be imaged with MRI and then diagnosed with an incisional biopsy. Patients with soft tissue sarcomas must be treated in an interdisciplinary collaboration so that they can undergo multimodal treatment. The proposed algorithm should help avoid delays in diagnosis and optimize treatment strategies.

Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity >50 IU/dl after cessation of any hemotherapy for >24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to 15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR =1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42], p Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.