Bad Homburg vor der Höhe, Germany
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Schlenk R.F.,University of Ulm | Taskesen E.,Erasmus University Rotterdam | Van Norden Y.,Erasmus University Rotterdam | Krauter J.,Hemostasis | And 21 more authors.
Blood | Year: 2013

The clinical value of allogeneic hematopoietic stem cell transplantation (alloHSCT) and autologous hematopoietic stem cell transplantation (autoHSCT) in the subtype of acute myeloid leukemia (AML) with double mutant CEBPA (CEBPAdm) has remained unsettled. Among 2983 patients analyzed for CEBPA mutational status (age 18-60 years) treated on 4 published Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) and 3 German-Austrian AML Study Group (AMLSG) protocols (2 published, 1 registered, clinicaltrials.gov NCT00151255), 124 had AML with CEBPAdm and achieved first complete remission (CR1). Evaluation of the clinical impact of alloHSCT and autoHSCT vs chemotherapy was performed by addressing time dependency in the statistical analyses. Thirty-two patients proceeded to alloHSCT from a matched related (MRD, n 5 29) or a matched unrelated donor (MUD, n 5 3), 20 to autoHSCT in CR1 and 72 received chemotherapy. Relapse-free survival was significantly superior in patients receiving an alloHSCT or autoHSCT in CR1 as compared with chemotherapy (P <.001), whereas overall survival was not different (P <.12). Forty-five patients relapsed. Of 42 patients treated with reinduction therapy, 35 achieved a second CR (83%) and most patients (n 5 33) received an alloHSCT MRD, n 5 11; MUD, n 5 19; haplo-identical donor, n 5 3). Survival of relapsed patients measured from date of relapse was 46% after 3 years. Adult AML patients with CEBPAdm benefit from alloHSCT and autoHSCT; relapsed patients still have a favorable outcome after reinduction followed by alloHSCT. © 2013 by The American Society of Hematology.


Grunig E.,University of Heidelberg | Lichtblau M.,University of Heidelberg | Ehlken N.,University of Heidelberg | Ghofrani H.A.,Justus Liebig University | And 15 more authors.
European Respiratory Journal | Year: 2012

The objective of this prospective study was to assess safety and efficacy of exercise training in a large cohort of patients with different forms and World Health Organization (WHO) functional classes of chronic pulmonary hypertension (PH). 183 patients with PH (pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH due to respiratory or left heart diseases received exercise training in hospital for 3 weeks and continued at home. Adverse events have been monitored during the in-hospital training programme. Efficacy parameters were evaluated at baseline, and after 3 and 15 weeks. After 3 and 15 weeks, patients significantly improved the distance walked in 6 min (6MWD) compared to baseline, scores of quality of life, WHO functional class, peak oxygen consumption, oxygen pulse, heart rate and systolic pulmonary artery pressure at rest and maximal workload. The improvement in 6MWD was similar in patients with different PH forms and functional classes. Even in severely affected patients (WHO functional class IV), exercise training was highly effective. Adverse events, such as respiratory infections, syncope or presyncope, occurred in 13% of patients. Exercise training in PH is an effective but not a completely harmless add-on therapy, even in severely diseased patients, and should be closely monitored. Copyright©ERS 2012.


Fehm T.,University of Tübingen | Muller V.,University of Hamburg | Aktas B.,University of Duisburg - Essen | Janni W.,Heinrich Heine University Düsseldorf | And 13 more authors.
Breast Cancer Research and Treatment | Year: 2010

There is a growing body of evidence that HER2 status can change during disease recurrence or progression in breast cancer patients. In this context, re-evaluation of HER2 status by assessment of HER2 expression on circulating tumor cells (CTCs) is a strategy with potential clinical application. The aim of this trial was to determine the HER2 status of CTCs in metastatic breast cancer patients comparing two CTC assays. A total of 254 patients with metastatic breast cancer from nine German university breast cancer centers were enrolled in this prospective study. HER2 status of CTCs was assessed using both the FDA-approved CellSearch® assay and AdnaTest BreastCancer™. Using the CellSearch assay, 122 of 245 (50%) patients had -5 CTCs, and HER2-positive CTCs were observed in 50 (41%) of these patients. Ninety of 229 (39%) patients were CTC positive using AdnaTest BreastCancer, and HER2 positivity rate was 47% (42 of 90). The rate of breast cancer patients with HER2-negative primary tumors but HER2-positive CTCs was 32% (25 of 78) and 49% (28 of 57) using the CellSearch assay and AdnaTest BreastCancer, respectively. Considering only those patients who had CTCs on both tests (n = 62), concordant results regarding HER2 positivity were obtained in 50% of the patients (31/62) (P = 0.96, κ = -0.006). HER2-positive CTCs can be detected in a relevant number of patients with HER2 negative primary tumors. Therefore, it will be mandatory to correlate the assay-dependent HER2 status of CTCs to the clinical response on HER2-targeted therapies. © 2010 Springer Science+Business Media, LLC.


Wick W.,University of Heidelberg | Wick W.,German Cancer Research Center | Wick W.,University of Tübingen | Platten M.,University of Heidelberg | And 22 more authors.
The Lancet Oncology | Year: 2012

Background: Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Methods: Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m2 temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6-7 weeks in 30 fractions of 1·8-2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Findings: Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3-10·2) in the temozolomide group versus 9·6 months (8·2-10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84-1·42, pnon-inferiority=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2-4·1] vs 4·7 [4·2-5·2]; HR 1·15, 95% CI 0·92-1·43, pnon-inferiority=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0-10·0]; HR 0·62, 95% CI 0·42-0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5-11·7] vs 4·6 [4·2-5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0-3·5] vs 4·6 months [3·7-6·3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Interpretation: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Funding: Merck Sharp & Dohme. © 2012 Elsevier Ltd.


Hourfar J.,Reinheim | Hourfar J.,University of Heidelberg | Ludwig B.,Traben Trarbach | Ludwig B.,University of Homburg | Kanavakis G.,Tufts University
Journal of Orthodontics | Year: 2014

Design: A single-centre, retrospective study was performed.Setting: Private orthodontic practice.Methods: 43 participants (20 males and 23 females) who had received treatment with the skeletally anchored 'Frog' appliance where included. In order to explore dentoalveolar and skeletal treatment outcomes, pre-(T1) and post-(T2) treatment measurements were performed on patients' plaster models and cephalometric images. Comparisons between T1 and T2 were made by means of a Student's t-test. All statistical analyses were conducted at the 0.05 level of statistical significance.Results: Study model analysis revealed a statistically significant derotation of maxillary molars (μΔT2-T159.5°, P<0.001) as well as an increase in transverse arch dimensions at the end of treatment (μΔT2-T152.2 mm, P<0.001). Cephalometric changes included bodily distalization of maxillary molars (μΔT2-T1=-1.9 mm, P<0.001), as well as noticeable angular displacement (μΔT2-T1= 4.1°, P50.004). No significant anchorage loss was observed, as displayed by the limited change in maxillary incisor position (μΔ(T2-T1)50.2 mm, P50.45). In addition, excellent vertical control of the maxillary molars was achieved, with no change in the mandibular plane (ML/NSL) angle (μΔT2-T1=0.3°, P=0.38).Conclusions: The skeletal 'Frog' is effective in derotating and distalizing maxillary molars without anchorage loss and with excellent vertical control.Participants: Patients who had undergone comprehensive orthodontic treatment with the skeletally anchored 'Frog' appliance.Objective: The objective of this investigation was to evaluate treatment outcomes of the skeletally anchored 'Frog' appliance. © 2014 British Orthodontic Society.


Dr. Anke Ott Young, Plastic Surgeon, Norma F. Pfriem Breast Cancer Center, has joined The Expert Network©, an invitation-only service for distinguished professionals. Dr. Young has been chosen as a Distinguished Doctor™ based on peer reviews and ratings, numerous recognitions, and accomplishments achieved throughout her career. Dr. Young outshines others in her field due to her extensive educational background, recognitions, and career longevity. After earning her medical degree from Saarland University in Saarbrücken, Germany, Dr. Young went on to complete an internship and residency at the Ear, Nose, and Throat Hospital at the University of Homburg where she also earned her doctorate in forensic psychiatry. She continued her training in medicine stateside with a general surgery residency at Long Island Jewish Hospital, followed by a plastic surgery residency and a fellowship in reconstructive microsurgery at the Memorial Sloan-Kettering Cancer Center. With 24 years dedicated to medicine, Dr. Young brings a wealth of knowledge to her industry and, in particular, to her area of expertise, plastic reconstructive and oncoplastic surgery. When asked why she decided to pursue a career in medicine, Dr. Young said: "I always had a very keen interest for the science of medicine and helping people. My grandmothers and great-grandmothers and great-great-grandmothers all were midwives, so I think I had some of that in my blood. For me, I think surgery is instant gratification. You see the results right away which works for my temperament. I also like doing things with my hands. My mother is a seamstress so I grew up knitting and doing all kinds of craftwork so it fits right in." Dr. Young currently practices with Yale New Haven Health’s Bridgeport Hospital and splits her time between the Norma F. Pfriem Breast Cancer Center in Fairfield, Connecticut and her office in Garden City, New York where she focuses Minimally Invasive Breast Cancer Reconstruction. As a thought-leader in her specialty, Dr. Young keeps a close eye on prevailing trends in plastic surgery in order to be able to provide her patients with the most advanced care available. Always at the forefront of her methodology is providing her patients with superlative care and comfort, which has contributed to and maintained her interest in microsurgery. Recently, Dr. Young has seen an increasing shift toward this emerging field, as well as toward other minimally invasive procedures. She noted: "The trend is to make surgeries less and less invasive. I have implemented this in my own practice. Breast reconstruction has traditionally never really been a minimally invasive procedure; for example, a traditional mastectomy reconstruction has always resulted in broken muscle and skin for the sake of adding a new breast. But now, technology is getting increasingly better and so breast surgery is as well. This new technology that specializes in breast surgery allows us to spare muscle and connective tissue as well as make skin incisions in the way that works for the plastic surgeon and patient. With the cooperation between the specialties we get much better results with much less invasive surgery." Dr. Young is a member of the American Medical Association, the Association of Plastic Surgeons, and the Northeastern Society of Plastic Surgeons. For more information, visit Dr. Young's profile on the Expert Network here: http://expertnetwork.co/members/anke-ott-young,-md,-phd/0f8a17151273cb72 The Expert Network© has written this news release with approval and/or contributions from Dr. Anke Ott Young. The Expert Network© is an invitation-only reputation management service that is dedicated to helping professionals stand out, network, and gain a competitive edge. The Expert Network© selects a limited number of professionals based on their individual recognitions and history of personal excellence.


Yu H.,Punchbowl | Yu H.,University of Hawaii at Manoa | Zhang Z.,Punchbowl | Zhang Z.,University of Hawaii at Manoa | And 7 more authors.
Cellular and Molecular Life Sciences | Year: 2013

Transient receptor potential melastatin 7 (TRPM7) is a divalent-selective cation channel fused to an atypical α-kinase. TRPM7 is a key regulator of cell growth and proliferation, processes accompanied by mandatory cell volume changes. Osmolarity-induced cell volume alterations regulate TRPM7 through molecular crowding of solutes that affect channel activity, including magnesium (Mg2+), Mg-nucleotides and a further unidentified factor. Here, we assess whether chloride and related halides can act as negative feedback regulators of TRPM7. We find that chloride and bromide inhibit heterologously expressed TRPM7 in synergy with intracellular Mg2+ ([Mg 2+]i) and this is facilitated through the ATP-binding site of the channel's kinase domain. The synergistic block of TRPM7 by chloride and Mg2+ is not reversed during divalent-free or acidic conditions, indicating a change in protein conformation that leads to channel inactivation. Iodide has the strongest inhibitory effect on TRPM7 at physiological [Mg 2+]i. Iodide also inhibits endogenous TRPM7-like currents as assessed in MCF-7 breast cancer cells, where upregulation of SLC5A5 sodium-iodide symporter enhances iodide uptake and inhibits cell proliferation. These results indicate that chloride could be an important factor in modulating TRPM7 during osmotic stress and implicate TRPM7 as a possible molecular mechanism contributing to the anti-proliferative characteristics of intracellular iodide accumulation in cancer cells. © 2013 Springer Basel.


Weide B.,University of Tübingen | Derhovanessian E.,University of Tübingen | Pflugfelder A.,University of Tübingen | Eigentler T.K.,University of Tübingen | And 5 more authors.
Cancer | Year: 2010

BACKGROUND: Systemic high-dose interleukin-2 (IL-2) achieved long-term survival in a subset of patients with advanced melanoma. The authors reported previously that intratumorally applied IL-2 induced complete local responses of all metastases in >60% of patients. The objectives of the current study were to confirm those results in a larger cohort and to identify patient or regimen characteristics associated with response. METHODS: Patients with melanoma who had a median of 12 injectable metastases received intratumoral IL-2 treatments 3 times weekly until they achieved clinical remission. The initial dose of 3 million international units was escalated, depending on the individual patient's tolerance. RESULTS: Forty-eight of 51 patients were evaluable. Only grade 1/2 toxicity was recorded. A complete response that lasted ≥6 months was documented in 70% of all injected metastases. A complete local response of all treated metastases was achieved in 33 patients (69%), including 11 patients who had between 20 and 100 metastases. Response rates were higher for patients who had stage III disease compared with patients who had stage IV disease. No objective responses of distant untreated metastases were observed. The 2-year survival rate was 77% for patients with stage IIIB/IIIC disease and 53% for patients with stage IV disease. Efficacy and survival did not differ between patients who had ≥20 lesions and patients who had <20 lesions. CONCLUSIONS: Intratumoral IL-2 treatment elicited complete local responses in a high percentage of patients. Further studies will be required to investigate the mode of action of this treatment and its impact on survival. © 2010 American Cancer Society.AdverseEffects:48 patients had side effects (injection site swelling 48, injection site erythema 48, injection site pain in unstated number, fever 28, fatigue 17, nausea 16, stomach pain 4, myalgia 4, headache 4, itching exanthema 3, dry oral mucosa 2, pruritus 2, hair loss 1, diarrhea 1, urticaria 1, exacerbation of atopic dermatitis 1, cardiac arrhythmia 1, vitiligo 1).FreeText:Previous therapies: surgery for metastatic disease (n=28), limb perfusion (n=2), radiotherapy (n=2), adjuvant interferon alpha (n=14), systemic chemotherapy (n=11). Concomitant medications: anesthetic cream and oral metamizole (number not stated), paracetamol (n=28), antihistamine (n=1). Tests: tumor response, sonography (to guide injections for deep soft tissue metastases and to evaluate subcutaneous metastases), tumor biopsy (for histopathologic confirmation of treatment response) and frequency of antimelanoma T cells by flow cytometry and interferon-gamma staining (n=1).Indications:48 patients with metastatic melanoma (dermal only 28, subcutaneous only 11, combined 9, stage IIIB 17, stage IIIC 16, Stage IV M1a 8, stage IV M1b 3, stage IV M1c 4, lymph node/visceral metastases 5). Coexisting disease: atopic dermatitis (1).Patients:48 outpatients, 21 males and 27 females aged between 37 and 88 years, median age 69 years. Duration of follow up was 4 to 68 months, median 25 months.TypeofStudy:Local response to intratumoral Proleukin was evaluated in patients with metastatic melanoma. Open multicenter study.DosageDuration:Initially 3 MIU daily intratumorally (sc or intradermally) that was escalated by 1.5 MIU each treatment day up to the desired total dose (the highest daily dose was 16 MIU) (minimal single dose per lesion: 0.3, 0.6, 1.2, 3.0 and 6.0 MIU intratumorally for lesions <2 mm, <5 mm, <10 mm, <20 mm and ≥20 mm, respectively). Median duration was 6 weeks (range, 1-32 weeks)Results:Proleukin was generally well tolerated, and only grade 1 and 2 toxicity was recorded. Outcome was complete response (CR) rate of 78.7%, partial response (PR) rate of 0.7%, 16.3% stable metastases, and 4.3% progressive lesions. Statistically significant differences were noted for rate of complete local responses of injected metastases between stages III vs. stage IV (96.9% vs. 54.8%, respectively) and the absence or presence of visceral metastases (92.5% vs. 16.5%, respectively). Efficacy differed significantly between dermal vs. subcutaneous injected lesions both for stage III disease (CR rate: 97.9% vs. 90.3%, respectively) and stage IV disease (CR rate: 56.7% vs. 34.4%, respectively). No objective responses of noninjected distant lesions were noted in 5 patients with stage IV disease and visceral metastases. One 59-year-old patient with stage IIIB melanoma (17 lesions) has remained progression free since the start of Proleukin in August 2003. An 88-year-old woman with stage IIIB (25 lesions) remained progression-free from the start of Proleukin in December 2004 until her death in January 2009. A 47-year-old woman with stage IV melanoma (M1a) (44 lesions) has remained progression free since June 2006. In 33 patients (69%) a local CR of all treated metastases was achieved with a better outcome for patients with stage III disease vs. stage IV disease (82% vs. 40%). 32 of these patients were completely free of recognizable tumor. No deaths were recorded from melanoma later than 25 months after starting Proleukin, suggesting a long-term survival in patients who survived the first 2 years. Patients who had stage III disease had higher overall survival rates vs. stage IV patients (77% vs. 53% after 2 years). Overall survival for patients who had stage IV disease without visceral metastases was comparable to that of stage III patients. The long-term outcome did not depend on the number of treated metastases. In 1 patient with stage III disease and 19 dermal metastases, who received 11 treatments (cumulative dose 55 MIU Proleukin), had an ongoing complete clinical and histopathologic response after therapy. There was a significant increase in IFN-γ-positive, CD8-positive T cells that were specific for MAGE-A3, Melan-A, and NY-ESO-1 during treatment, and the increased frequency of MAGE-A3-specific, CD8-positive T cells remained present 2 months after the end of treatment; whereas the frequency of influenza-specific, IFN-γ-positive T cells remained constant at all 3 time points. There was a marked increase in the frequency of IFN-γ-positive, CD4-positive T cells that were specific for MAGE-A3 during and after therapy, but the frequency of CD4-positive T cells that were specific for other antigens did not change significantly.AuthorsConclusions:In conclusion, intratumoral IL-2 [interleukin-2] treatment elicited complete local responses of all injected lesions in 69% of patients, especially in patients without visceral metastases. A high proportion of patients could be rendered completely free of injected metastases using this approach. A large number of metastases were not associated with a poorer long-term outcome. Therefore, intratumoral IL-2 may be regarded as a promising therapeutic option for a selected subgroup of patients with melanoma and also may be feasible for the treatment of other accessible solid tumor entities. Further studies will be required to investigate the mode of action and the impact on survival of intratumoral treatment with IL-2.


Weide B.,University of Tübingen | Eigentler T.K.,University of Tübingen | Pflugfelder A.,University of Tübingen | Leiter U.,University of Tübingen | And 6 more authors.
Cancer Immunology, Immunotherapy | Year: 2011

Systemic high-dose interleukin-2 (IL-2) treatment achieves long-term survival in a subset of advanced patients with melanoma. As we reported previously, intratumoral IL-2 induced complete local responses in more than 60% of melanoma patients. This study aimed to analyze the long-term outcome of 72 patients treated in two prior trials. Melanoma patients (49 stage III, 23 stage IV) with injectable metastases received intratumoral IL-2 injections thrice weekly at individually escalated doses (median duration, 6.5 weeks; median total IL-2 dose, 72 MIU; median number of injected metastases, 10). The observed 2-year overall survival rates were 95.5% for stage III patients with cutaneous metastases only (stage IIIB), 72% for those with combined cutaneous and lymph node involvement (stage IIIC), 66.7% for stage IV patients with disease limited to distant soft-tissue metastases (stage IV M1a), and 9.1% for those with visceral metastases (stage IV M1b and stage IV M1c). Thirty patients who reported recurrence of unresectable distant metastases subsequently received chemotherapy in the further course of disease and showed an overall response rate of 36.7% (16.7% complete responses, 20% partial responses). A high total dose of IL-2 and a dacarbazine/temozolomide-based chemotherapy regimen were variables correlated with a clinical response. In conclusion, patients with cutaneous metastasis without lymph node involvement in stage III and with soft-tissue metastasis without visceral involvement in stage IV showed unexpected favorable survival rates after intratumoral treatment with IL-2. Furthermore, the intratumoral IL-2 treatment seemed to be associated with increased complete and partial responses in subsequent chemotherapies. © 2010 Springer-Verlag.

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