Krefeld, Germany
Krefeld, Germany

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Felgentreff K.,University Hospital Freiburg | Perez-Becker R.,Helios Hospital Krefeld | Speckmann C.,University Hospital Freiburg | Schwarz K.,University Hospital Freiburg | And 8 more authors.
Clinical Immunology | Year: 2011

Hypomorphic mutations in genes associated with severe combined immunodeficiency (SCID) or Omenn syndrome can also cause milder immunodeficiencies. We report 10 new patients with such "atypical" SCID and summarize 63 patients from the literature. The patient groups with T lowB low (n=28), T lowB + (n=16) and ADA (n=29) SCID variants had similar infection profiles but differed in the frequency of immune dysregulation, which was observed predominantly in patients with recombination defects. Most immunological parameters were remarkably similar in the three groups. Of note, 19/68 patients with "atypical" SCID had normal T cell counts, 48/68 had normal IgG and 23/46 had at least one normal specific antibody titer. Elevated IgE was a characteristic feature of ADA deficiency. This overview characterizes "atypical" SCID as a distinct disease with immune dysregulation in addition to infection susceptibility. Lymphopenia, reduced naïve T cells and elevated IgE are suggestive, but not consistent features of the disease. © 2011 Elsevier Inc.


Zimmermann H.,University of Kiel | Reinke P.,Charité - Medical University of Berlin | Neuhaus R.,Charité - Medical University of Berlin | Lehmkuhl H.,German Heart Institute Berlin | And 9 more authors.
Cancer | Year: 2012

BACKGROUND: Burkitt lymphoma post-Transplantation lymphoproliferative disorder (Burkitt-PTLD) is a rare form of monomorphic B-cell PTLD for which no standard treatment has been established. Currently, the treatment of Burkitt lymphoma outside the post-Transplantation setting involves high doses of alkylating agents, frequent dosing, and intrathecal and/or systemic central nervous system prophylaxis. In PTLD, however, such protocols are associated with considerable toxicity and mortality. METHODS: The authors present a retrospective series of 8 adult patients with Burkitt-PTLD. Six patients were reported to the prospective German PTLD registry or were enrolled in the PTLD-1 trial, and 2 patients had received treatment before 2000, thus allowing for comparison with the pre-rituximab era. RESULTS: Seven of the 8 patients were men. The median age at presentation was 38 years, and the median time since transplantation was 5.7 years. Five of 8 patients had histologically established, Epstein-Barr virus-associated disease, and 7 of 7 patients were positive for a MYC translocation. Five of 8 patients received sequential immunochemotherapy (4 courses of rituximab [R] followed by 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] or R plus CHOP [R-CHOP]). In this group, 5 of 5 patients reached complete remission (CR), and their overall survival (OS) was significantly longer (P =.008) compared with the OS for 2 of 8 patients who received first-line CHOP and did not respond. One of 8 patients (who had stage IV disease with meningiosis) received combination therapy (cyclophosphamide pretreatment, rituximab, intrathecal chemotherapy, whole-brain irradiation, and radioimmunotherapy) and reached CR. Overall, 6 of 8 patients reached CR; and, after a median follow-up of 4.7 years (range, 1.7-4.8 years), the median OS was 36.7 months. There was no treatment-related mortality under first-line therapy. CONCLUSIONS: In the largest adult case series in Burkitt-PTLD to date, sequential immunochemotherapy with rituximab followed by standard CHOP or R-CHOP was a both safe and effective treatment. © 2012 American Cancer Society.


Beikert F.C.,University of Hamburg | Anastasiadou Z.,University of Hamburg | Fritzen B.,HELIOS Hospital Krefeld | Frank U.,University of Heidelberg | Augustin M.,University of Hamburg
Dermatology | Year: 2013

Background: The antifungal activity of coriander oil has already been demonstrated in vitro. Objective: Evaluation of the efficacy and tolerability of 6% coriander oil in unguentum leniens in the treatment of interdigital tinea pedis. Methods: Half-side comparative pilot study on subjects with symmetric, bilateral interdigital tinea pedis. Active drug and placebo control were applied twice daily on the affected areas, and follow-up visits were performed on days 14 and 28. Results: 40 participants (mean age 52.5 years, 60% male) were included in the study. For 6% coriander oil in unguentum leniens, a highly significant improvement of the clinical signs (p < 0.0001) was observed during the entire observation period; the number of positive fungal cultures also tended to decrease (p = 0.0654). The tolerability of the tested substances was good. Conclusion: Coriander oil is effective and well tolerated in the treatment of interdigital tinea pedis. © 2013 S. Karger AG, Basel.


Rink M.,University of Hamburg | Rink M.,Cornell University | Chun F.K.,University of Hamburg | Dahlem R.,University of Hamburg | And 12 more authors.
European Urology | Year: 2012

Background: Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB). Objective: Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB. Design, setting, and participants: Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization. Intervention: Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy. Measurements: Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis. Results and limitations: CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1-100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size. Conclusions: Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials. © 2012 European Association of Urology.


Tolsdorff B.,University of Würzburg | Pommert A.,MAN Group | Hohne K.H.,MAN Group | Petersik A.,MAN Group | And 3 more authors.
Laryngoscope | Year: 2010

Objectives/Hypothesis: Virtual surgical training systems are of growing value. Current prototypes for endonasal sinus surgery simulation are very expensive or lack running stability. No reliable system is available to a notable number of users yet. The purpose of this work was to develop a dependable simulator running on standard PC hardware including a detailed anatomic model, realistic tools and handling, stereoscopic view, and force feedback. Study Design: Descriptive. Methods: A three-dimensional voxel model was created based on a high-resolution computed tomography study of a human skull, from which the bony structures were segmented. The mucosa and organs at risk were added manually. The model may be manipulated with virtual surgical tools controlled with a low-cost haptic device, which is also used to adjust microscopic or endoscopic views. Visualization, haptic rendering, and tissue removal are represented with subvoxel resolution. Results: The handling of the model is convincing. The haptic device provides a realistic feeling regarding the interaction between tool tip and anatomy. Three-dimensional orientation and the look and feel of virtual surgical interventions get close to reality. Conclusions: The newly developed system is a stable, fully operational simulator for sinus surgery based on standard PC hardware. Besides the limitations of a low-cost haptic device, the presented system is highly realistic regarding anatomy, visualization, manipulation, and the appearance of the tools. It is mainly intended for gaining surgical anatomy knowledge and for training navigation in a complex anatomical environment. Learning effects, including motor skills, have yet to be quantified. © 2009 The American Laryngological, Rhinological and Otological Society, Inc.


Rink M.,University of Hamburg | Chun F.K.H.,University of Hamburg | Minner S.,University of Hamburg | Friedrich M.,University of Hamburg | And 6 more authors.
BJU International | Year: 2011

What's known on the subject? and What does the study add? Circulating tumour cells (CTC) have prognostic relevance for patients with different metastatic carcinomas. Detection of CTC using the CellSearch system has also been reported in bladder cancer, but mainly in patients with metastatic disease. This is the largest report demonstrating that detection of CTC in non-metastatic bladder cancer patients is feasible using the CellSearch system. Presence of CTC may be predictive for early systemic disease. OBJECTIVE To prospectively detect and evaluate the biological significance of circulating tumour cells (CTC) in patients with bladder cancer, especially in those patients with non-metastatic, advanced bladder cancer (NMABC). PATIENTS AND METHODS Between July 2007 and January 2009, blood samples of 50 consecutive patients with localized bladder cancer and five patients with metastatic disease scheduled for cystectomy were prospectively investigated for CTC. Peripheral blood (7.5 ml) was drawn before cystectomy. Detection of CTC was performed using the USA Food and Drug Administration-approved CellSearch TM system. Data were compared with the clinical and histopathological findings. RESULTS CTC were detected in 15 of 50 patients (30%) with non-metastatic disease and five of five patients with metastatic disease. The overall mean number of CTC was 33.7 (range: 1-372; median: 2). In non-metastatic patients, the mean number of CTC was 3.1 (range: 1-11; median: 1). Except for a univariate association between CTC with vessel infiltration (P= 0.047), all other common clinical and histopathological parameters did not reveal a significant correlation with CTC detection. A median 1-year follow up was available for 53 patients (96.4%). Ten out of 19 preoperatively CTC-positive patients died as a result of cancer progression. CTC-positive patients showed significantly worse overall (P= 0.001), progression-free (P < 0.001) and cancer specific survival (P < 0.001) compared to preoperatively CTC-negative patients. CONCLUSION This is the largest study demonstrating that detection of CTC in NMABC patients is feasible using the CellSearch TM system. Our findings suggest that the presence of CTC may be predictive for early systemic disease. © 2010 The Authors.


Thill M.,University of Lübeck | Terjung A.,HELIOS Hospital Krefeld | Friedrich M.,HELIOS Hospital Krefeld
European Journal of Gynaecological Oncology | Year: 2014

Up until now there have been many advances in treatment options for breast cancers such as targeted therapies like monoclonal antibodies, tyrosine kinase inhibitors, mTOR antagonists, and vaccines. Despite these advances, there are still many more that warrant further exploration. Two of these targets might be the cyclooxygenase-2 (COX-2), the key enzyme required to convert arachidonic acid to prostaglandins, and calcitriol [1,25(OH)2D3] which is the biologically active form of vitamin D. Both calcitriol and the inhibition of COX-2 have shown antiproliferative and prodifferentiation, as well as pro-apoptotic effects in different malignancies in vitro and in vivo, and the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is known to have tumor suppressor activity. Furthermore, the combination of calcitriol and nonsteroidal anti-inflammatory drugs (NSAIDs), such as non-selective and selective COX-2 inhibitors, acting synergistically to achieve significant cell growth inhibition in prostate cancer. Some epidemiological studies suggest that vitamin D confers a moderate benefit against breast cancer while most epidemiological studies presume that NSAIDs confer the same. Nevertheless there is growing body of evidence that COX-2 expression is a fundamental step in breast cancer carcinogenesis. To date, clinical trials have been conducted in patients with different malignancies using treatment strategies including COX-2 inhibitors and calcitriol and are showing partially encouraging results. The goal of this review is to shed light on the association between the prostaglandin as well as vitamin D metabolism relating to the incidence and therapy of breast cancers. Moreover, this review will also highlight potential treatment options, as well as extract any existing interactions between the two metabolisms.


Wojcinski S.,Hannover Medical School | Stefanidou N.,Helios Hospital Krefeld | Hillemanns P.,Hannover Medical School | Degenhardt F.,Franziskus Hospital Bielefeld
BMC Women's Health | Year: 2013

Background: The aim of this study was to evaluate the relation of some ultrasound morphological parameters to biological characteristics in breast carcinoma.Methods: Ultrasound data from 315 breast masses were collected. We analyzed the ultrasound features of the tumors according to the ACR BI-RADS®-US classification system stratified by hormone receptor status, HER2 status, histology grade, tumor type (ductal versus lobular), triple-negativity, breast density, tumor size, lymph node involvement and patient's age.Results: We found a variety of ultrasound features that varied between the groups. Invasive lobular tumors were more likely to have an angulated margin (39% versus 22%, p = 0.040) and less likely to show posterior acoustic enhancement (3% versus 16%, p = 0.023) compared to invasive ductal carcinoma. G3 tumors were linked to a higher chance of posterior acoustic enhancement and less shadowing and the margin of G3 tumors was more often described as lobulated or microlobulated compared to G1/G2 tumors (67% versus 46%, p = 0.001). Tumors with an over-expression of HER2 exhibited a higher rate of architectural distortions in the surrounding tissue, but there were no differences regarding the other features. Hormone receptor negative tumors were more likely to exhibit a lobulated or microlobulated margin (67% versus 50%, p = 0.037) and less likely to have an echogenic halo (39% versus 64%, p = 0.001). Furthermore, the posterior acoustic feature was more often described as enhancement (33% versus 13%, p = 0.001) and less often as shadowing (20% versus 47%, p < 0.001) compared to hormone receptor positive tumors.Conclusion: Depending on their biological and clinical profile, breast cancers are more or less likely to exhibit the typical criteria for malignancy in ultrasound. Moreover, certain types of breast cancer tend to possess criteria that are usually associated with benign masses. False-negative diagnosis may result in serious consequences for the patient. For the sonographer it is essential to be well aware of potential variations in the ultrasound morphology of breast tumors, as described in this paper. © 2013 Wojcinski et al.; licensee BioMed Central Ltd.


Thill M.,AGAPLESION Markus Hospital | Kraft C.,Helios Hospital Krefeld | Friedrich M.,Helios Hospital Krefeld
Oncology Research and Treatment | Year: 2016

Categorization, risk assessment, and treatment of breast cancer have been revolutionized by the original description of the human epidermal growth factor receptor 2 (HER2), first as a prognostic marker and then as a therapeutic target. The HER2-positive subtype of breast cancer represents less than approximately 20% of the incident breast cancers. Nevertheless, many lessons can be learned from the development of anti-HER2 therapies in early-stage disease. This review will comment on the key studies in both the (neo)adjuvant and metastatic settings and discusses some of the controversies that still remain today both in clinical care and as research questions. © 2016 S. Karger GmbH, Freiburg.


Eichenmuller M.,Ludwig Maximilians University of Munich | Hemmerlein B.,University of Gottingen | Hemmerlein B.,HELIOS Hospital Krefeld | Von Schweinitz D.,Ludwig Maximilians University of Munich | Kappler R.,Ludwig Maximilians University of Munich
British Journal of Cancer | Year: 2010

Background:Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with the ability to resist apoptosis by the activation of survival promoting and anti-apoptotic proteins.Methods:Efficacy of the apoptosis-inducing agent betulinic acid (BA) was determined in RMS cell cultures and in vivo by measuring cell viability, survival, apoptosis, hedgehog signalling activity, and neovascularisation.Results:Betulinic acid had a strong cytotoxic effect on RMS cells in a dose-dependent manner. The BA treatment caused a massive induction of apoptosis mediated by the intrinsic mitochondrial pathway, which could be inhibited by the broad-range caspase inhibitor zVAD.fmk. Exposure of hedgehog-activated RMS-13 cells to BA resulted in a strong decrease in GLI1, GLI2, PTCH1, and IGF2 expression as well as hedgehog-responsive luciferase activity. Intraperitoneal injection of 20 mg BA per kg per day significantly retarded growth of RMS-13 xenografts in association with markedly higher counts of apoptotic cells and down-regulation of GLI1 expression compared with control tumours, while leaving microvascular density, cell proliferation, and myogenic differentiation unaffected.Conclusion:Our data show that induction of apoptosis and inhibition of hedgehog signalling are important features of the anti-tumourigenic effect of BA in RMS and advices this compound for the use in a multimodal therapy of this highly aggressive paediatric tumour. © 2010 Cancer Research UK All rights reserved.

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