D'Abramo F.,Charite Comprehensive Cancer Center
Journal of Epidemiology and Community Health | Year: 2015
With the rise of -omics disciplines and biobank research, personal data and biosamples crossing national borders pose new ethical questions. In this article, informed consent, as originally conceived, is shown as not being sufficient to address aims of research and interests of patients any more. Therefore the author has, after having scrutinised issues in biobanking, sketched a model of dynamic consent and a manner of scrutinising ethical issues through empirical data.
Kretschmer C.,Research Group Surgical Oncology |
Sterner-Kock A.,University of Cologne |
Siedentopf F.,DRK Kliniken Berlin Westend |
Schoenegg W.,DRK Kliniken Berlin Westend |
And 2 more authors.
Molecular Cancer | Year: 2011
Background: The ductal carcinoma in situ (DCIS) of the mammary gland represents an early, pre-invasive stage in the development of invasive breast carcinoma. Since DCIS is a curable disease, it would be highly desirable to identify molecular markers that allow early detection. Mice transgenic for the WAP-SV40 early genome region were used as a model for DCIS development. Gene expression profiling was carried out on DCIS-bearing mice and control animals. Additionally, a set of human DCIS and invasive mammary tumors were analyzed in a similar fashion. Enhanced expression of these marker genes in human and murine samples was validated by quantitative RT-PCR. Besides, marker gene expression was also validated by immunohistochemistry of human samples. Furthermore in silico analyses using an online microarray database were performed.Results: In DCIS-mice seven genes were identified that were significantly up-regulated in DCIS: DEPDC1, NUSAP1, EXO1, RRM2, FOXM1, MUC1 and SPP1. A similar up-regulation of homologues of the murine genes was observed in human DCIS samples. Enhanced expression of these genes in DCIS and IDC (invasive ductal carcinoma) was validated by quantitative RT-PCR and immunohistochemistry.Conclusions: By comparing murine markers for the ductal carcinoma in situ (DCIS) of the mammary gland with genes up-regulated in human DCIS-samples we were able to identify a set of genes which might allow early detection of DCIS and invasive carcinomas in the future. The similarities between gene expression in DCIS and invasive carcinomas in our data suggest that the early detection and treatment of DCIS is of utmost relevance for the survival of patients who are at high risk of developing breast carcinomas. © 2011 Kretschmer et al; licensee BioMed Central Ltd.
Goerling U.,Charite Comprehensive Cancer Center |
Stickel A.,Charite Comprehensive Cancer Center
Recent Results in Cancer Research | Year: 2014
Continuous improvements in the diagnosis and treatment of cancer lead to improved cure rates and longer survival. However, in many patients, the disease becomes chronic. In this context, the patients’ quality of life (QOL) becomes a crucial issue. After an introduction about QOL, results from different areas of cancer treatment are presented considering their impact on QOL. Finally, implications are discussed for researchers, clinicians, and patients. © 2014, Springer-Verlag Berlin Heidelberg.
Khoja L.,The Christie NHS Foundation Trust |
Lorigan P.,The Christie NHS Foundation Trust |
Dive C.,Paterson Institute for Cancer Research |
Keilholz U.,Charite Comprehensive Cancer Center |
And 2 more authors.
Annals of Oncology | Year: 2015
Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
Church T.R.,University of Minnesota |
Wandell M.,Rice University |
Lofton-Day C.,Epigenomics Inc. |
Mongin S.J.,University of Minnesota |
And 9 more authors.
Gut | Year: 2014
Background: As screening methods for colorectal cancer (CRC) are limited by uptake and adherence, further options are sought. A blood test might increase both, but none has yet been tested in a screening setting. Objective: We prospectively assessed the accuracy of circulating methylated SEPT9 DNA (mSEPT9) for detecting CRC in a screening population. Design: Asymptomatic individuals ≥50 years old scheduled for screening colonoscopy at 32 US and German clinics voluntarily gave blood plasma samples before colon preparation. Using a commercially available assay, three independent blinded laboratories assayed plasma DNA of all CRC cases and a stratified random sample of other subjects in duplicate real time PCRs. The primary outcomes measures were standardised for overall sensitivity and specificity estimates. Results: 7941 men (45%) and women (55%), mean age 60 years, enrolled. Results from 53 CRC cases and from 1457 subjects without CRC yielded a standardised sensitivity of 48.2% (95% CI 32.4% to 63.6%; crude rate 50.9%); for CRC stages I-IV, values were 35.0%, 63.0%, 46.0% and 77.4%, respectively. Specificity was 91.5% (95% CI 89.7% to 93.1%; crude rate 91.4%). Sensitivity for advanced adenomas was low (11.2%). Conclusions: Our study using the blood based mSEPT9 test showed that CRC signal in blood can be detected in asymptomatic average risk individuals undergoing screening. However, the utility of the test for population screening for CRC will require improved sensitivity for detection of early cancers and advanced adenomas. Clinical Trial Registration Number: NCT00855348.
Wang Q.,Experimental Clinical Research Center at the Max Delbrueck |
Ma C.,Experimental Clinical Research Center at the Max Delbrueck |
Kemmner W.,Experimental Clinical Research Center at the Max Delbrueck |
Kemmner W.,Charite Comprehensive Cancer Center
BMC Cancer | Year: 2013
Background: We attempted to identify novel biomarkers and therapeutic targets for esophageal squamous cell carcinoma by gene expression profiling of frozen esophageal squamous carcinoma specimens and examined the functional relevance of a newly discovered marker gene, WDR66.Methods: Laser capture microdissection technique was applied to collect the cells from well-defined tumor areas in collaboration with an experienced pathologist. Whole human gene expression profiling of frozen esophageal squamous carcinoma specimens (n = 10) and normal esophageal squamous tissue (n = 18) was performed using microarray technology. A gene encoding WDR66, WD repeat-containing protein 66 was significantly highly expressed in esophageal squamous carcinoma specimens. Microarray results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in a second and independent cohort (n = 71) consisting of esophageal squamous cell carcinoma (n = 25), normal esophagus (n = 11), esophageal adenocarcinoma (n = 13), gastric adenocarcinoma (n = 15) and colorectal cancers (n = 7). In order to understand WDR66's functional relevance siRNA-mediated knockdown was performed in a human esophageal squamous cell carcinoma cell line, KYSE520 and the effects of this treatment were then checked by another microarray analysis.Results: High WDR66 expression was significantly associated with poor overall survival (P = 0.031) of patients suffering from esophageal squamous carcinomas. Multivariate Cox regression analysis revealed that WDR66 expression remained an independent prognostic factor (P = 0.042). WDR66 knockdown by RNA interference resulted particularly in changes of the expression of membrane components. Expression of vimentin was down regulated in WDR66 knockdown cells while that of the tight junction protein occludin was markedly up regulated. Furthermore, siRNA-mediated knockdown of WDR66 resulted in suppression of cell growth and reduced cell motility.Conclusions: WDR66 might be a useful biomarker for risk stratification of esophageal squamous carcinomas. WDR66 expression is likely to play an important role in esophageal squamous cell carcinoma growth and invasion as a positive modulator of epithelial-mesenchymal transition. Furthermore, due to its high expression and possible functional relevance, WDR66 might be a novel drug target for the treatment of squamous carcinoma. © 2013 Wang et al.; licensee BioMed Central Ltd.
Schirrmacher V.,German Cancer Research Center |
Fournier P.,German Cancer Research Center |
Schlag P.,Charite Comprehensive Cancer Center
Expert Review of Vaccines | Year: 2014
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Surgery remains the primary curative treatment but nearly 50% of patients relapse as consequence of micrometastatic or minimal residual disease (MRD) at the time of surgery. Spontaneous T-cell-mediated immune responses to CRC tumor-associated antigens (TAAs) in tumor-draining lymph nodes and in the bone marrow (BM) lead to infiltration of the tumors by lymphocytes. Certain types of such tumor-infiltrating lymphocytes (TILs) have a positive and others a negative impact on the patients' prognosis. This review focuses on advances in CRC active-specific immunotherapy (ASI), in particular on results from randomized controlled clinical studies employing therapeutic autologous tumor cell vaccines. The observed improvement of long-term survival is explained by activation and mobilization of a pre-existing repertoire of tumor-reactive memory T cells which, according to recent discoveries, reside in distinct niches of patients' bone marrow in neighborhood with hematopoietic (HSC) and mesenchymal (MSC) stem cells. Interestingly, memory T cells also contain a subset of stem memory T cells (SMTs) in addition to effector (EMTs) and central memory T cells (CMTs). The mechanism of function of a therapeutic vaccine in a chronic disease is distinct from that of prophylactic vaccines which have to generate de novo protective immune responses. The advantage of autologous vaccines for mobilization of a broad and highly individual repertoire of memory T cells will be discussed. © Informa UK, Ltd.
Burock S.,Charite Comprehensive Cancer Center |
Herrmann P.,Max Delbrück Center for Molecular Medicine |
Wendler I.,Charité - Medical University of Berlin |
Niederstrasser M.,Charité - Medical University of Berlin |
And 2 more authors.
World Journal of Gastroenterology | Year: 2015
AIM: To evaluate the diagnostic and prognostic value of circulating Metastasis Associated in Colon Cancer 1 (MACC1) transcripts in plasma of gastric cancer patients. METHODS: We provide for the first time a blood-based assay for transcript quantification of the metastasis inducer MACC1 in a prospective study of gastric cancer patient plasma. MACC1 is a strong prognostic biomarker for tumor progression and metastasis in a variety of solid cancers. We conducted a study to define the diagnostic and prognostic power of MACC1 transcripts using 76 plasma samples from gastric cancer patients, either newly diagnosed with gastric cancer, newly diagnosed with metachronous metastasis of gastric cancer, as well as follow-up patients. Findings were controlled by using plasma samples from 54 tumor-free volunteers. Plasma was separated, RNA was isolated, and levels of MACC1 as well as S100A4 transcripts were determined by quantitative RT-PCR. RESULTS: Based on the levels of circulating MACC1 transcripts in plasma we significantly discriminated tumorfree volunteers and gastric cancer patients (P < 0.001). Levels of circulating MACC1 transcripts were increased in gastric cancer patients of each disease stage, compared to tumor-free volunteers: patients with tumors without metastasis (P = 0.005), with synchronous metastasis (P = 0.002), with metachronous metastasis (P = 0.005), and patients during follow-up (P = 0.021). Sensitivity was 0.68 (95%CI: 0.45-0.85) and specificity was 0.89 (95%CI: 0.77-0.95), respectively. Importantly, gastric cancer patients with high circulating MACC1 transcript levels in plasma demonstrated significantly shorter survival when compared with patients demonstrating low MACC1 levels (P = 0.0015). Furthermore, gastric cancer patients with high circulating transcript levels of MACC1 as well as of S100A4 in plasma demonstrated significantly shorter survival when compared with patients demonstrating low levels of both biomarkers or with only one biomarker elevated (P = 0.001). CONCLUSION: Levels of circulating MACC1 transcripts in plasma of gastric cancer patients are of diagnostic value and are prognostic for patient survival in a prospective study. © The Author(s) 2015.
Juneja M.,Max Delbrück Center for Molecular Medicine |
Ilm K.,Max Delbrück Center for Molecular Medicine |
Schlag P.M.,Max Delbrück Center for Molecular Medicine |
Schlag P.M.,Charite Comprehensive Cancer Center |
Stein U.,Max Delbrück Center for Molecular Medicine
Molecular Oncology | Year: 2013
MACC1, Metastasis associated in colon cancer 1, is a newly identified prognostic biomarker for colorectal cancer metastasis and patient survival, when determined in the primary tumor or patient blood. MACC1 induces cell motility and proliferation in cell culture and metastasis in mouse models. MACC1 acts as a transcriptional regulator of the receptor tyrosine kinase gene Met via binding to its promoter. However, no information about the promoter of the MACC1 gene and its transcriptional regulation has been reported so far. Here we report the identification of the MACC1 promoter using a promoter luciferase construct that directs transcription of MACC1. To gain insights into the essential domains within this promoter region, we constructed 5' truncated deletion constructs. Our results show that the region from -426 to -18 constitutes the core promoter and harbors functional motifs for the binding of AP-1, Sp1, and C/EBP transcription factors as validated by site directed mutagenesis study. Using electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we demonstrated the physical interaction of these transcription factors to a minimal essential MACC1 core promoter sequence. Knock down of these transcription factors using RNAi strategy reduced MACC1 expression (P<0.001), and resulted in decrease of cell migration (P<0.01) which could be specifically rescued by ectopic overexpression of MACC1. In human colorectal tumors, expression levels of c-Jun and Sp1 correlated significantly to MACC1 (P=0.0007 and P=0.02, respectively). Importantly, levels of c-Jun and Sp1 also showed significant correlation to development of metachronous metastases (P=0.01 and P=0.001, respectively). This is the first study identifying the MACC1 promoter and its transcriptional regulation by AP-1 and Sp1. Knowledge of the transcriptional regulation of the MACC1 gene will implicate in enhanced understanding of its role in cancer progression and metastasis. © 2013 Federation of European Biochemical Societies.
Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): An open-label, randomised phase 3 trial
Machiels J.P.H.,Catholic University of Leuven |
Haddad R.I.,Dana-Farber Cancer Institute |
Fayette J.,University of Lyon |
Licitra L.F.,Fondazione IRCCS Instituto Nazionale Tumori |
And 15 more authors.
The Lancet Oncology | Year: 2015
Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. Methods: In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2 per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. Findings: Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. Interpretation: Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. Funding: Boehringer Ingelheim. © 2015 Elsevier Ltd.