Witzel I.,University of Hamburg |
Loibl S.,Forschungs GmbH |
Von Minckwitz G.,Forschungs GmbH |
Mundhenke C.,University of Kiel |
And 14 more authors.
Breast Cancer Research and Treatment | Year: 2010
In the context of neoadjuvant therapy (NT) for breast cancer patients, different targeted therapy approaches are currently evaluated in clinical trials. Serum markers could help to monitor and optimize such treatment strategies. We investigated human epidermal growth factor receptor 2 serum (sHER2) levels in 175 breast cancer patients participating in the GeparQuattro trial. This study incorporated NT approaches and additional trastuzumab treatment for all patients with HER2-positive tumors. Human epidermal growth factor receptor 2 serum levels were measured by enzyme-linked immunosorbent assay (ELISA) before initiation of NT and after NT (pre-surgery) in a HER2-positive (n = 90) and a HER2-negative patient cohort (n = 85). Median pre-chemotherapy sHER2 levels were higher in patients with positive HER2 status of the primary tumor than in patients with negative HER2 status (14.9 ng/ml vs. 7.7 ng/ml, P < 0.001). A pre-chemotherapy sHER2 cut-off level of 10 ng/ml had the best sensitivity and specificity in discriminating between HER2-positive and HER2-negative primary tumors. In HER2-positive patients, we found a significant positive association between pathological complete remission (pCR) and elevated sHER2 levels (above 15 ng/ml, P = 0.045) and a decrease of sHER2 levels during NT (P = 0.02), which was also significant in multivariate analysis (OR = 3.29, 95% CI 1.001-10.89, P = 0.049). In HER2-negative patients, we observed no association between sHER2 levels and pCR (P > 0.05). Monitoring sHER2 levels in the presence of anti-HER2 treatment might be an adjunct to the clinical evaluation during NT. © 2010 Springer Science+Business Media, LLC.
Seidel M.F.,Medizinische Klinik und Poliklink I |
Herguijuela M.,Seidel Klinik |
Forkert R.,Johanniter Krankenhaus |
Otten U.,University of Basel
Seminars in Arthritis and Rheumatism | Year: 2010
Objectives: The nervous system modulates the immune response in many autoimmune syndromes by neurogenic inflammation. One of the pivotal mediators is nerve growth factor (NGF), which is known for its effects on neuronal survival and growth. There is considerable evidence that NGF acts as an important mediator of many immune responses. This article reviews the role of NGF in rheumatic diseases and strategies for potential therapeutic interventions. Methods: We conducted a database search using Medline and Medpilot. Eight hundred abstracts containing the keyword NGF and 1 of the following terms were reviewed: arthritis, neurogenic inflammation, rheumatoid arthritis, osteoarthritis, collagen arthritis, arteritis, psoriasis, psoriatic arthritis, Sjogren syndrome, systemic lupus erythematosus, gout, osteoporosis, lower back pain, lumbar disc herniation, nerve root compression, spondyloarthritis, spondylarthropathy, algoneurodystrophy, fibromyalgia, Kawasaki syndrome, polyarteritis nodosa, cytokine, vasculitis, pain, therapy, and antagonist. Articles were analyzed based on relevance and content. Most clinical trials and studies with human specimens were included. Studies with experimental animal models were selected if they contained relevant data. Results: NGF is overexpressed in many inflammatory and degenerative rheumatic diseases. Concentrations differ to some extent and sometimes even show contradictory results. NGF is found in serum, synovial fluid, and cerebrospinal fluid, and tissue specimens. NGF concentrations can be correlated with the extent of inflammation and/or clinical activity in many conditions. In rheumatoid arthritis, NGF levels are significantly higher as compared with osteoarthritis. Conclusions: NGF is a significant mediator and modulator of inflammation. NGF sometimes shows detrimental and sometimes regenerative activity. These findings indicate potential therapeutic interventions using either NGF antagonists or recombinant NGF. © 2010 Elsevier Inc.
Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: Final results of a randomised phase 3 trial of the arbeitsgemeinschaft internistische onkologie (AIO-PK0104)
Heinemann V.,Ludwig Maximilians University of Munich |
Vehling-Kaiser U.,Practice for Medical Oncology |
Waldschmidt D.,University of Cologne |
Marten A.,University of Heidelberg |
And 16 more authors.
Gut | Year: 2013
AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine. Methods 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients. Results Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/ erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2e4:2.9/4.3/ 6.7 months, p<0.0001) and survival (3.4/7.0/ 9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, ps0.005). Conclusion Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.
PubMed | Johanniter Krankenhaus and University of Bochum
Type: Journal Article | Journal: International journal of medical sciences | Year: 2014
Although chronic pulmonary hypertension and right ventricular (RV) function carry important functional and prognostic implications in idiopathic dilated cardiomyopathy (IDC), little information on RV muscle mass (RVMM) and its determinants has been published.Our study comprised thirty-five consecutive patients with IDC, left ventricular (LV) ejection fraction<40% and NYHA class2. Hemodynamic data and parameters on LV and RV geometry were derived from right heart catheterisation and cardiac magnetic resonance imaging.RVMM was normalized to body size using a common linear, body surface area based approach (RVMMI) and by an allometric index (RVMM-AI) incorporating adjustment for age, height and weight. Stepwise multiple regression analysis revealed that pulmonary artery pressure and left ventricular muscle mass were independent predictors of RVMM-AI. The interventricular mass ratio of RV and LV mass (IVRM) was closely related to RVMM (r=0.79, p<0.001) and total muscle mass (r=0.39, p<0.02). However, there was no significant relationship between LVMM and IVMR (r=0.17, p=0.32).Our data suggest that an increase in RV mass in IDC may be explained by two mechanisms: First, as a consequence of the myopathic process itself resulting in a balanced hypertrophy of both ventricles. Second, due to the chamber specific burden of pulmonary artery pressure rise, resulting in unbalanced RV hypertrophy.
Von Minckwitz G.,C o GBG Forschungs GmbH |
Darb-Esfahani S.,Charité - Medical University of Berlin |
Loibl S.,C o GBG Forschungs GmbH |
Huober J.,Breast Center |
And 15 more authors.
Breast Cancer Research and Treatment | Year: 2012
Adjacent ductal carcinomainsitu (DCIS)isfound in approximately 45% of invasive ductal carcinomas (IDC) of the breast. Pure DCIS overexpresses HER2 in approximately 45%. There is uncertainty whether adjacent DCIS impacts on the responsetoneoadjuvant chemotherapyand trastuzumabas well as whether HER2 expression in IDC component or adjacent DCIS changes throughout treatment. Core biopsies and surgical tissue from participants of the GeparQuattro study with HER2-positive IDC were centrally examined for the area of invasive ductal component and adjacent DCIS before and after receiving neoadjuvant anthracycline-taxane-trastuzumab containing chemotherapy. HER2 overexpression in IDC and adjacent DCIS was quantified separately by immunohistochemistry using the Ventana ™ automated staining system. Pathological complete response (pCR) was defined as no residual invasive or non-invasive tumor tissue. Fifty-nine (37.3%) of 158 IDCs presented with adjacent DCIS at diagnosis. These tumors showed lower regression grades than pure IDC (P = 0.033). The presence of adjacent DCIS was an independent negative predictor of pCR [odds ratio 0.42 (95% CI 0.2-0.9), P = 0.027]. Adjacent DCIS area decreased from pre-treatment to surgery (r = 0.205) with 30 (50.8%) IDCs with adjacent DCIS showing complete eradication of adjacent DCIS. HER2 status of adjacent DCIS was highly correlated with HER2 status of IDC component before (r = 0.892) and after treatment (r = 0.676). Degree of HER2 overexpression of the IDC component decreased in 16 (33.3%) out of 49 patients without a pCR. These 16 IDCs showed lower RGs compared to the 33 IDCs with unchanged HER2 expression (P = 0.055). HER2-positive IDCs with adjacent DCIS is less responsive to neoadjuvant chemotherapy and trastuzumab compared to pure IDC. However, complete eradication of adjacent DCIS is frequently observed. HER2-overexpression of the invasive ductal component decreases in a subset of tumors, which showed less tumor regression. © Springer Science+Business Media, LLC. 2011.
Vormbrock J.,Ruhr University Bochum |
Liebeton J.,Ruhr University Bochum |
Wirdeier S.,Ruhr University Bochum |
Meissner A.,Ruhr University Bochum |
And 3 more authors.
International Journal of Medical Sciences | Year: 2014
Introduction: Although chronic pulmonary hypertension and right ventricular (RV) function carry important functional and prognostic implications in idiopathic dilated cardiomyopathy (IDC), little information on RV muscle mass (RVMM) and its determinants has been published. Methods: Our study comprised thirty-five consecutive patients with IDC, left ventricular (LV) ejection fraction <40% and NYHA class ≥2. Hemodynamic data and parameters on LV and RV geometry were derived from right heart catheterisation and cardiac magnetic resonance imaging. Results: RVMM was normalized to body size using a common linear, body surface area based approach (RVMMI) and by an allometric index (RVMM-AI) incorporating adjustment for age, height and weight. Stepwise multiple regression analysis revealed that pulmonary artery pressure and left ventricular muscle mass were independent predictors of RVMM-AI. The interventricular mass ratio of RV and LV mass (IVRM) was closely related to RVMM (r = 0.79, p < 0.001) and total muscle mass (r = 0.39, p < 0.02). However, there was no significant relationship between LVMM and IVMR (r = 0.17, p = 0.32). Conclusion: Our data suggest that an increase in RV mass in IDC may be explained by two mechanisms: First, as a consequence of the myopathic process itself resulting in a balanced hypertrophy of both ventricles. Second, due to the chamber specific burden of pulmonary artery pressure rise, resulting in unbalanced RV hypertrophy. © Ivyspring International Publisher.
Stubs P.,Otto Von Guericke University of Magdeburg |
Habermann P.,Johanniter Krankenhaus |
Wex C.,Otto Von Guericke University of Magdeburg |
Mohren M.,Johanniter Krankenhaus |
And 3 more authors.
Zentralblatt fur Chirurgie - Zeitschrift fur Allgemeine, Viszeral- und Gefasschirurgie | Year: 2010
Background: There are a number of effective substances available for palliative treatment of colorectal cancer, contributing to a considerable extension of the median survival time either purely medically or by increasing the chance of secondary resectability through improved effectiveness of the administered drugs. Patients/Material:Defining treatment depending on predominant patient characteristics remains crucial for any therapeutic success. This requires interdisciplinary co-ordination within tumour boards. Methods:In aggressive tumours a therapeutic approach inducing high response rates is favoured, usually including a triple or quadruple combination incl. antibodies. In cases of slow tumour progress and limited patient profile, a sequence of chemotherapy is chosen. Implementing and integrating locally ablative modes of therapy into the treatment strategy can increase the effectiveness additionally. In a best case scenario additional systemic side effects can be avoided resulting in a not insignificant benefit in quality of life. Results:Further genotyping beyond the K-RAS state is necessary to make predictive and prognostic statements concerning the drugs applied and to avoid ineffectiveness. Conclusion:Considerable progress has been achieved in the medical therapy for metastasised colorectal cancer. The targeted application of already available as well as recently developed substances requires further evaluation by appropriate studies. © Georg Thieme Verlag KG Stuttggart · New York.
Grafenstein K.,Johanniter Krankenhaus
Aktuelle Rheumatologie | Year: 2011
The involvement of the lungs in connective tissue diseases is often underestimated, which also depends on the type of diagnostic methods used. We have studied 3 groups of diseases, diffuse systemic sclerosis and limited systemic sclerosis and overlap syndromes, interstitial lung changes and pulmonary arterial hypertension as the main pulmonary manifestations. The 6-minute walking test and the CO diffusion capacity showed the limitations of the lung function at best. The HR-CT is a method for the assessment of lung structure changes and should be supplemented by BAL and histology for therapeutic decisions to influence the pulmonary fibrosis. A PAH can be determined by using Doppler echocardiography. Echocardiographic criteria for pulmonary hypertension are the tricuspid pressure gradient, the size of the right atrium, the size of the right ventricle and the tricuspid annular plane systolic excursion (TAPSE). Right heart catherisation is necessary for the definite diagnosis of pulmonary hypertension and the final therapeutic decision. At the end of the study all diagnostic methods were ranked regarding their importance. © Georg Thieme Verlag KG Stuttgart.
Ponisch W.,University of Leipzig |
Bourgeois M.,University of Leipzig |
Moll B.,University of Leipzig |
Heyn S.,University of Leipzig |
And 18 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013
Introduction: Bortezomib (Velcade®) is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in multiple myeloma (MM). In the present protocol, bortezomib was combined with other active substances like bendamustine and prednisone (BPV), in order to assess the efficacy and toxicity of the combination therapy in patients with relapsed or refractory MM. Methods: Between January 2005 and December 2011, 78 patients with relapsed or refractory MM were treated with bendamustine 60 (-120) mg/m2 on days 1 and 2, bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11. The median number of prior therapies was 2 with a wide range of 1-9. Thirty-three patients had pre-existing severe thrombocytopenia and/or neutropenia (WHO grade 3 or 4). Results: A median number of two (range 1-7) BPV treatment cycles were given to the patients. The majority of the patients (n = 54; 69 %) responded after at least one cycle of chemotherapy with 3 CR, 10 nCR, 10 VGPR and 31 PR. Median PFS and OS for patients without severe hematological toxicities due to previous treatments (n = 45) were 11 and 50 months, respectively. Outcome for these patients was significantly better than that for patients with severe hematological toxicities (grade 3 or 4, n = 33) with a PFS, and OS of 3 months (p < 0.05) and 5 months (p < 0.001), respectively. The regimen was well tolerated with few significant side effects in patients without severe hematological toxicities due to previous treatments. Summary: These results indicate that the combination of bortezomib, bendamustine and prednisone is well tolerated in patients with relapsed or refractory MM. © 2012 Springer-Verlag Berlin Heidelberg.