Marienhospital Darmstadt

Darmstadt, Germany

Marienhospital Darmstadt

Darmstadt, Germany

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Moehler M.,Johannes Gutenberg University Mainz | Delic M.,Johannes Gutenberg University Mainz | Goepfert K.,Johannes Gutenberg University Mainz | Aust D.,Carl Gustav Carus Institute | And 13 more authors.
European Journal of Cancer | Year: 2016

The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient's tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies. © 2016 Elsevier Ltd. All rights reserved.


PubMed | University of Leipzig, Autonomous University of Barcelona, Carl Gustav Carus Institute, University of Lausanne and 9 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of CancerGastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectalcancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancerhas been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patients tumour with vaccines produced on demand. Other strategies considering checkpointinhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies.


Hoensch H.,Marienhospital Darmstadt | Richling E.,University of Kaiserslautern | Kruis W.,Evangelisches Krankenhaus Cologne Kalk | Kirch W.,TU Dresden
Medizinische Klinik | Year: 2010

Background: Valid, sustained and safe clinical means of colorectal cancer prevention are still lacking, but they are urgently needed to lower the incidence of colorectal cancer. Dietary factors and phytochemicals such as flavonoids play an important role for prevention. Methods: A selective search of the literature using PubMed was performed with the following key words: flavonoids, cancer, therapy, colorectal cancer focused on clinical queries. Results of clinical studies including the authors' own were compared. Results: In vivo and in vitro studies with animals, cell cultures and subcellular components provide ample evidence for antimutagenic and anticarcinogenic effects of flavonoids as shown for multiple biological and molecular endpoints. Isoflavonoids in vitro have been shown to induce proliferation of breast cancer cells. Epidemiologic trials (cohort, case-control and cross-sectional studies) yielded inconsistent results for flavonoid protection. Systematic reviews and meta-analyses support the protective role of tea flavonoids on adenoma incidence. An interventional pilot study with sustained flavonoid supplementation was shown to reduce the rate of neoplasia in patients with resected colorectal cancer. Conclusion: Selected flavonoids possess antimutagenic and anticarcinogenic properties and could reduce the incidence of colorectal neoplasias as shown in epidemiologic trials. Randomized controlled clinical studies with flavonoid intervention are necessary to provide evidence for their role in colorectal cancer prevention. © 2010 Urban & Vogel.


Merx K.,University of Heidelberg | Barreto Miranda M.,Marienhospital Darmstadt | Kellermann L.,Oncology Information Service OIS | Mahlknecht U.,St. Lukas Klinik | And 3 more authors.
Gastroenterology Research and Practice | Year: 2016

We analysed trends over time in palliative first-line chemotherapy in patients with locally advanced or metastatic esophagogastric cancer. Special focus was on frequency and quality of HER2-testing and trends in drug use in combination with trastuzumab. Earlier published data about patients treated outside clinical studies showed a relatively low rate of HER2-testing and insufficient test quality. A total of 2,808 patients retrospectively documented in Therapiemonitor® from 2006 to 2013 were analysed regarding treatment intensity and trends in used drugs. Data on HER2-testing and therapies were analysed in two cohorts documented in 2010 and 2011 (1) compared to 2012 and 2013 (2). Treatment intensity increased: 49.3% of patients received at least a triplet in 2013 compared to 10.1% in 2006. In cohort 2 HER2 expression was tested in 79.1% of the cases. Still, in 26.9% testing was not done as requested by guidelines. Good performance status, multiple metastases, age ≤ 65 years, the objective "to prevent progression," good cognitive capabilities, estimated good compliance, and social integration positively influenced the probability of HER2-testing; comorbidities negatively affected it. Usage of the combination of fluoropyrimidines and cisplatin with trastuzumab declined from 67% in cohort 1 to 50% in cohort 2. Copyright © 2016 Kirsten Merx et al.


Moehler M.,Johannes Gutenberg University Mainz | Maderer A.,Johannes Gutenberg University Mainz | Schimanski C.,Marienhospital Darmstadt | Kanzler S.,Leopoldina Hospital | And 21 more authors.
European Journal of Cancer | Year: 2014

Background Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. Patients and methods 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). Results Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS. Conclusion The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment. © 2014 The Authors. Published by Elsevier Ltd.


Allami R.H.,Johannes Gutenberg University Mainz | Graf C.,Johannes Gutenberg University Mainz | Martchenko K.,Marienhospital Darmstadt | Voss B.,Johannes Gutenberg University Mainz | And 6 more authors.
Oncology Letters | Year: 2016

C-X-C motif chemokine ligand 12 (CXCL12), also termed stromal cell-derived factor-1 (SDF-1) is a small protein 8-14 kDa in length that is expressed as six isoforms, consisting of SDF-1α, SDF-1β, SDF-1γ, SDF-1δ, SDF-1ε and SDF-1θ. All six isoforms are encoded by the single CXCL12 gene on chromosome 10. This gene regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. The potential role of the novel CXCL12 splice variants as components of the CXCR4 axis in cancer development is not fully understood. The present study aimed to analyze the expression profile of the various SDF-1 isoforms and SDF-1 polymorphisms, and the association with the clinicopathological features and overall survival of patients with colorectal cancer (CRC). SDF-1 polymorphism analysis was performed using restriction fragment length polymorphism (RFLP) analysis in 73 histologically confirmed human CRC tissue samples at various stages of disease. The expression pattern of the SDF-1 isoforms was analyzed by reverse transcription-polymerase chain reaction in 40 histologically confirmed human CRC tissue samples obtained at various stages of disease, as well as in matched adjacent normal mucosa samples. The presence of the CXCL12 gene polymorphism rs1801157 demonstrated an association with local progression of the primary tumor, as indicated by the T stage. The frequency of the GG genotype was slightly increased in patients with stage 3 and 4 tumors (78.0%) compared with the incidence of the GA/AA genotype (69.5%; P=0.067). The expression of SDF-1β was associated with the presence of metastases (P=0.0656) and the expression of SDF-1γ was significantly associated with tumor size (P=0.0423). The present study is the first to analyze the association between the expression profile of the chemokine CXCL12 splice variants in human CRC tissues and their clinical relevance. The present results reveal that the CXCL12 G801A polymorphism is a low-penetrance risk factor for the development of CRC, and was associated with the T stage. All six isoforms of SDF-1 were expressed in CRC tissues. The expression of SDF-1β was found to be associated with metastases and SDF-1γ appears to be a possible tumor marker for local tumor progression. © Spandidos Publications 2016.


Wehler T.C.,Johannes Gutenberg University Mainz | Graf C.,Johannes Gutenberg University Mainz | Mohler M.,Johannes Gutenberg University Mainz | Herzog J.,Marienhospital Darmstadt | And 7 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013

Purpose: Treatment with cetuximab is accompanied by the development of an acneiform follicular skin exanthema in more than 80 % of patients. Severe exanthema (grade III/IV) develops in about 9-19 % of patients with the necessity of cetuximab dose reduction or cessation. Methods: The study presented was a retrospective analysis of 50 gastrointestinal cancer patients treated with cetuximab in combination with either FOLFIRI or FOLFOX. One cohort of 15 patients received an in-house reactive skin protocol upon development of an exanthema. A second cohort of 15 patients received a skin prophylaxis starting with the first dose of cetuximab before clinical signs of toxicity. A third historic group of 20 patients had received no skin prophylaxis or reactive treatment. Results: 19/20 patients of the historic group developed a skin exanthema. Grade III/IV exanthema was observed six times. Forty percent discontinued cetuximab therapy. The average time to exanthema onset was 14.7 days. Applying the reactive skin protocol after the first occurrence of an exanthema, the exanthema was downgraded as follows: No patients developed grade IV exanthema, and two patients developed a grade II/III exanthema. In the majority of cases, the reactive skin protocol controlled the exanthema (grade 0-I). No dose reductions in cetuximab were necessary. Applying the prophylactic skin protocol starting at the beginning of cetuximab application was not superior to the reactive skin protocol. Conclusions: Cetuximab-induced skin exanthema can be coped with a reactive protocol equally effective as compared to a prophylactic skin treatment. A prospective study with higher patient numbers is planned. © 2013 The Author(s).


PubMed | Johannes Gutenberg University Mainz, Marienhospital Darmstadt and German Cancer Research Center
Type: Journal Article | Journal: Oncology letters | Year: 2016

C-X-C motif chemokine ligand 12 (CXCL12), also termed stromal cell-derived factor-1 (SDF-1) is a small protein 8-14 kDa in length that is expressed as six isoforms, consisting of SDF-1, SDF-1, SDF-1, SDF-1, SDF-1 and SDF-1. All six isoforms are encoded by the single CXCL12 gene on chromosome 10. This gene regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. The potential role of the novel CXCL12 splice variants as components of the CXCR4 axis in cancer development is not fully understood. The present study aimed to analyze the expression profile of the various SDF-1 isoforms and SDF-1 polymorphisms, and the association with the clinicopathological features and overall survival of patients with colorectal cancer (CRC). SDF-1 polymorphism analysis was performed using restriction fragment length polymorphism (RFLP) analysis in 73 histologically confirmed human CRC tissue samples at various stages of disease. The expression pattern of the SDF-1 isoforms was analyzed by reverse transcription-polymerase chain reaction in 40 histologically confirmed human CRC tissue samples obtained at various stages of disease, as well as in matched adjacent normal mucosa samples. The presence of the CXCL12 gene polymorphism rs1801157 demonstrated an association with local progression of the primary tumor, as indicated by the T stage. The frequency of the GG genotype was slightly increased in patients with stage 3 and 4 tumors (78.0%) compared with the incidence of the GA/AA genotype (69.5%; P=0.067). The expression of SDF-1 was associated with the presence of metastases (P=0.0656) and the expression of SDF-1 was significantly associated with tumor size (P=0.0423). The present study is the first to analyze the association between the expression profile of the chemokine CXCL12 splice variants in human CRC tissues and their clinical relevance. The present results reveal that the CXCL12 G801A polymorphism is a low-penetrance risk factor for the development of CRC, and was associated with the T stage. All six isoforms of SDF-1 were expressed in CRC tissues. The expression of SDF-1 was found to be associated with metastases and SDF-1 appears to be a possible tumor marker for local tumor progression.


Hoensch H.P.,Marienhospital Darmstadt | Oertel R.,TU Dresden
Clinical Nutrition Experimental | Year: 2015

Flavonoids are phytochemicals and belong to the polyphenols. A wide variety of beneficial factors has been attributed to their mode of action. Some of their activities concerns the inhibition of inflammatory pathways and the down regulation of genes involved in chronic inflammatory disease states. These genes enhance the inflammatory signaling pathways leading to expression of inflammatory cytokines and chemokines. Flavonoids from fruits, vegetable and tea compounds can block many proinflammatory proteins and thus function as natural inhibitors of inflammation. Instead of using nonsteroidal anti-inflammatory drugs natural inhibitors could possibly be used to suppress the intensity of the inflammation in the chronically inflamed mucosa in patients with chronic inflammatory bowel disease. Natural inhibitors like flavonoids are xenobiotics which are metabolized by the cytochrome P-450 enzymes and conjugating protective enzymes. Flavonoids can induce these protective enzymes by upregulation and thereby could act as protective metabolic barrier within the intestinal mucosa. The nutritional value of flavonoids is probably related to their anti-inflammatory activity and through this mechanism responsible for prevention of neoplasia. The evidence for their clinical efficacy as essential compounds is still preliminary at best and limited but suggestive. © 2015 The Authors.


Hoensch H.,Marienhospital Darmstadt | Oertel R.,TU Dresden
Deutsche Medizinische Wochenschrift | Year: 2012

Tea flavonoids belong to the large group of polyphenols and display antioxidative, anti-inflammatory and anti-neoplastic activities. These phytochemicals are xenobiotics and are synthesized by tea plants such as Camellia sinensis and Camomilla recucita. These botanicals exhibit in vivo activities similar to that of biologicals which are widely used for chronic inflammatory diseases (rheumatoid arthritis, chronic inflammatory bowel disease). Epigallocathechin gallate and apigenin from these plants inhibit cytokines, chemokines and activated immune cells in vivo and in vitro. Clinical disorders with induced inflammatory pathways could benefit from flavonoid treatment. Dietary supplementation with specific tea-flavonoids could be used for Crohn's disease, ulcerative colitis and irritable bowel syndrome. Suppression of cytokine production could ultimately lead to inhibition of carcinogenesis. This mechanism could explain why flavonoids are effective in the prevention of intestinal neoplasia. This innovative new form of therapy should be tested in controlled, randomized clinical studies.© Georg Thieme Verlag KG · Stuttgart.

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