Publications by authors named "Georg Sauer"

28 Publications

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The INTREST registry: protocol of a multicenter prospective cohort study of predictors of women's response to integrative breast cancer treatment.

BMC Cancer 2021 Jun 23;21(1):724. Epub 2021 Jun 23.

Department of Psychology, Chair of Research Methodology and Statistics in Psychology, Witten / Herdecke University, Witten, Germany.

Background: Cancer registries usually assess data of conventional treatments and/or patient survival. Beyond that, little is known about the influence of other predictors of treatment response related to the use of complementary therapies (CM) and lifestyle factors affecting patients' quality and quantity of life.

Methods: INTREST is a prospective cohort study collecting register data at multiple German certified cancer centers, which provide individualized, integrative, in- and outpatient breast cancer care. Patient-reported outcomes and clinical cancer data of anticipated N = 715 women with pTNM stage I-III breast cancer are collected using standardized case report forms at the time of diagnosis, after completing neo-/adjuvant chemotherapy, after completing adjuvant therapy (with the exception of endocrine therapy) as well as 1, 2, 5, and 10 years after baseline. Endpoints for multivariable prediction models are quality of life, fatigue, treatment adherence, and progression-based outcomes/survival. Predictors include the study center, sociodemographic characteristics, histologic cancer and comorbidity data, performance status, stress perception, depression, anxiety, sleep quality, spirituality, social support, physical activity, diet behavior, type of conventional treatments, use of and belief in CM treatments, and participation in a clinical trial. Safety is recorded following the Common Terminology Criteria for Adverse Events.

Discussion: This trial is currently recruiting participants. Future analyses will allow to identify predictors of short- and long-term response to integrative breast cancer treatment in women, which, in turn, may improve cancer care as well as quality and quantity of life with cancer.

Trial Registration: German Clinical Trial Register DRKS00014852 . Retrospectively registered at July 4th, 2018.
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http://dx.doi.org/10.1186/s12885-021-08468-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220783PMC
June 2021

Gene Expression Signatures of BRCAness and Tumor Inflammation Define Subgroups of Early-Stage Hormone Receptor-Positive Breast Cancer Patients.

Clin Cancer Res 2020 12 2;26(24):6523-6534. Epub 2020 Oct 2.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.

Purpose: Patients with estrogen receptor- and/or progesterone receptor-positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches.

Experimental Design: From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors, gene expression analyses of 612 tumors was performed using the NanoString Breast Cancer 360 panel to interrogate 23 breast cancer pathways. Candidate signatures associated with disease subtype and event-free survival (EFS) were obtained by cluster analysis, Cox modeling, and conditional inference trees, and were independently tested in 613 patients from BreastMark. Tumor-infiltrating lymphocytes (TIL) were assessed on tissue sections, and mutational burden was assessed in 36 tumors by whole-exome sequencing.

Results: PAM50-derived classification distinguished lower-risk (Luminal A) from higher-risk subtypes (Luminal B, = 0.04; HER2, = 0.006; Basal, = 0.008). In higher-risk patients, shorter EFS was associated with low androgen receptor [HR = 3.61; 95% confidence interval (CI), 1.72-7.56; = 0.001] or high BRCAness signature expression (HR = 3.58; 95% CI, 1.19-10.7; = 0.023). BRCAness was independently confirmed as a predictor of shorter EFS (HR = 2.64; 95% CI, 1.31-5.34; = 0.007). About 13%-15% of patients, enriched for high-grade, higher-risk subtypes ( ≤ 0.0001), had strong expression of the Tumor Inflammation Signature (TIS) suggestive of an inhibited antitumor immune response. TIS scores were strongly associated with TIL numbers ( < 1e-30) but not with tumor mutation status.

Conclusions: BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1923DOI Listing
December 2020

[Impact of surgical approach on prognosis in early-stage cervical cancer].

Strahlenther Onkol 2019 03;195(3):274-276

MVZ im Fürstenberg-Karree, Institut für Zytologie Dysplasie, Hohenzollerndamm 123, 14199, Berlin, Deutschland.

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http://dx.doi.org/10.1007/s00066-019-01426-9DOI Listing
March 2019

[Present hormonal birth control and the risk of breast cancer].

Authors:
Georg Sauer

Strahlenther Onkol 2018 11;194(11):1066-1068

Abteilung Gynäkologie und Geburtshilfe, Robert-Bosch-Krankenhaus, Auerbachstr. 110, 70376, Stuttgart, Deutschland.

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http://dx.doi.org/10.1007/s00066-018-1372-5DOI Listing
November 2018

Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest.

Cancer Res 2016 05 24;76(10):2868-75. Epub 2016 Mar 24.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.

Although hyperthermia offers clinical appeal to sensitize cells to chemotherapy, this approach has been limited in terms of long-term outcome as well as economic and technical burden. Thus, a more detailed knowledge about how hyperthermia exerts its effects on chemotherapy may illuminate ways to improve the approach. Here, we asked whether hyperthermia alters the response to chemotherapy-induced DNA damage and whether this mechanism is involved in its sensitizing effect in BRCA-competent models of ovarian and colon cancer. Notably, we found that hyperthermia delayed the repair of DNA damage caused by cisplatin or doxorubicin, acting upstream of different repair pathways to block histone polyADP-ribosylation (PARylation), a known effect of chemotherapy. Furthermore, hyperthermia blocked this histone modification as efficiently as pharmacologic inhibitors of PARP (PARPi), producing comparable delay in DNA repair, induction of double-strand breaks (DSB), and cell cytotoxicity after chemotherapy. Mechanistic investigations indicated that inhibiting PARylation by either hyperthermia or PARPi induced lethal DSB upon chemotherapy treatment not only by reducing DNA repair but also by preventing replication fork slowing. Overall, our work reveals how PARP blockade, either by hyperthermia or small-molecule inhibition, can increase chemotherapy-induced damage in BRCA-competent cells. Cancer Res; 76(10); 2868-75. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2908DOI Listing
May 2016

Identification of alternative transcripts of rat CD9 expressed by tumorigenic neural cell lines and in normal tissues.

Genet Mol Biol 2013 Jul 22;36(2):276-81. Epub 2013 Jun 22.

Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany .

CD9 is the best-studied member of the tetraspanin family of transmembrane proteins. It is involved in various fundamental cellular processes and its altered expression is a characteristic of malignant cells of different origins. Despite numerous investigations confirming its fundamental role, the heterogeneity of CD9 or other tetraspanin proteins was considered only to be caused by posttranslational modification, rather than alternative splicing. Here we describe the first identification of CD9 transcript variants expressed by cell lines derived from fetal rat brain cells. Variant mRNA-B lacks a potential translation initiation codon in the alternative exon 1 and seems to be characteristic of the tumorigenic BT cell lines. In contrast, variant mRNA-C can be translated from a functional initiation codon located in its extended exon 2, and substantial amounts of this form detected in various tissues suggest a contribution to CD9 functions. From the alternative sequence of variant C, a different membrane topology (5 transmembrane domains) and a deviating spectrum of functions can be expected.
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http://dx.doi.org/10.1590/S1415-47572013000200019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715295PMC
July 2013

Molecular indicators of non-sentinel node status in breast cancer determined in preoperative biopsies by multiplexed sandwich immunoassays.

J Cancer Res Clin Oncol 2011 Aug 24;137(8):1175-84. Epub 2011 Apr 24.

Department of Obstetrics and Gynaecology, University of Ulm, Prittwitzstr. 43, 89075 Ulm, Germany.

Purpose: Purpose of this study was to determine the accuracy of prediction of non-sentinel lymph node (NSLN) involvement in sentinel node (SLN)-positive breast cancer patients based on protein concentrations measured in lysates from initially taken breast biopsies.

Methods: Data on protein expression, previously generated by multiplexed bead-based immunoassays, were analysed by multivariate logistic regression to define parameter sets of value to predict NSLN involvement. Receiver-operator characteristics (ROCs) were calculated as indicators of diagnostic significance.

Results: Analyses of data from all patients (n = 99) resulted in parameter sets that allowed direct prediction of the NSLN status with a ROC area under the curve (AUC) of 0.83. The clinically most relevant prediction of NSLN status in SLN-positive patients (n = 37) based on only seven parameters (including TIMP-2 as the most relevant single value) was possible with high accuracy indicated by an AUC of 0.89.

Conclusions: Parallel assessment of protein concentrations in breast biopsies is a highly promising approach to predict nodal involvement and even the NSLN status in SLN-negative breast cancer patients. Such diagnostic information could substantially reduce the number of completion axillary lymph node dissections in clinical practice.
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http://dx.doi.org/10.1007/s00432-011-0982-4DOI Listing
August 2011

Multiplexed immunoassays for the analysis of breast cancer biopsies.

Anal Bioanal Chem 2010 Aug 18;397(8):3329-38. Epub 2010 Jul 18.

NMI, Natural and Medical Sciences Institute, University of Tuebingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany.

Within the last decade, protein microarray technology has been successfully used for the simultaneous quantification of target proteins from minimal amounts of samples in basic and applied proteome research. The robustness and appropriate sensitivity of these miniaturized assays have been demonstrated and thus the transfer to routine and high-throughput applications is now possible. In this study, multiplexed bead-based sandwich immunoassays were used to determine the concentrations of 54 protein analytes, including HER 2 and the estrogen receptor, from ultrasound-guided large-core needle biopsies (LCNBs) from breast cancer patients. Expression levels for HER 2, estrogen receptors and progesterone receptors were also assessed by immunohistochemical routine staining, performed in the clinic on corresponding biopsy samples. The high concordance of the data sets generated with the bead-based protein arrays and by conventional immunohistochemical assessment of HER 2 and the estrogen receptor expressed by breast cancer cells present in the biopsies was demonstrated.
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http://dx.doi.org/10.1007/s00216-010-3873-7DOI Listing
August 2010

Differential expression of tetraspanin CD9 in basal cell and squamous cell carcinomas of the skin and actinic keratosis.

Oncol Lett 2010 Jan 1;1(1):37-40. Epub 2010 Jan 1.

Department of Ophthalmology, University Hospital Heidelberg, Heidelberg.

Tetraspanins are potentially useful molecular markers that differentiate between tumour classes and subtypes, since members of this protein family were often found to be altered during malignant conversion and tumour progression. In this study, we analysed expression of the tetraspanin CD9 in the frequent cutaneous neoplasms basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK), which is considered a precursor lesion (carcinoma in situ) from which an invasive SCC can develop. A moderate to strong CD9-specific staining of the tumour cells' plasma membranes was uniquely observed in all BCCs, SCCs and AKs. All SCCs showed additional intracellular CD9 which was rarely (20%) seen in AKs. Semi-quantitative assessment of CD9 present in the plasma membranes of tumour cells of BCCs (mean staining intensity 1.91) and SCCs (3.64) reflected the different CD9 expression of normal precursor cells from which these tumours most likely originate. Although considered an intermediate stage in the development of SCCs, AKs did not show intense staining of the plasma membranes typical of normal keratinocytes or invasive SCCs (p=0.011) but only moderate intensity (mean 1.63). In BCCs, significantly (p=0.0005, n=56) stronger CD9-specific immunoreactivity was seen in the inner regions of the tumours than at their sites of expansion. In summary, our results point to an important role of CD9 at the front of tumour expansion in BCCs and SCCs, and in the pathogenesis of invasive SCCs.
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http://dx.doi.org/10.3892/ol_00000006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436406PMC
January 2010

Glycosylation of tetraspanin Tspan-1 at four distinct sites promotes its transition through the endoplasmic reticulum.

Protein Pept Lett 2009 ;16(10):1244-8

Department of Obstetrics and Gynaecology, University of Ulm, Germany.

We showed that Tspan-1, a tetraspanin overexpressed in many human cancers, harbours oligosaccharides at all four potential N-glycosylation sites. Its most abundant form contained only mannose-rich sugar chains but two distinct glycosylation sites could also contain complex carbohydrates. Glycosylation seemed to be required for correct folding and subsequent transition through the endoplasmic reticulum.
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http://dx.doi.org/10.2174/092986609789071234DOI Listing
February 2010

Tspan-1 is a tetraspanin preferentially expressed by mucinous and endometrioid subtypes of human ovarian carcinomas.

Cancer Lett 2009 Mar 18;275(2):198-203. Epub 2008 Nov 18.

IZKF Laboratory for Microarray Applications, University of Würzburg, Germany.

In many human cancers, tumor progression was found to be associated with an altered expression of tetraspanins, a group of transmembrane adaptor proteins that are implicated in fundamental cellular processes. Although recognized as a characteristic of malignant cells of various origins, Tspan-1 has not yet been characterized in detail due to lack of specific antibodies. We describe the generation of Tspan-1-specific antibodies and immunohistochemical staining of different subtypes of ovarian carcinomas (n=72) that revealed significant differences in Tspan-1 expression that was pronounced in mucinous and endometrioid tumors. The observation that immunoreactivity was focused in intracellular vesicles often concentrated at the luminal sides of glandular structures further supported the assumption that Tspan-1 is involved in secretory pathways. In the group of serous ovarian carcinomas, pronounced expression of Tspan-1 was observed in FIGO stage III C-classified tumors of advanced stages. In summary, our results show that Tspan-1 is an important characteristic of malignant ovarian cancer cells and a potential therapeutic target.
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http://dx.doi.org/10.1016/j.canlet.2008.10.014DOI Listing
March 2009

Prediction of nodal involvement in breast cancer based on multiparametric protein analyses from preoperative core needle biopsies of the primary lesion.

Clin Cancer Res 2008 Jun;14(11):3345-53

Department of Obstetrics and Gynaecology, University of Ulm, Germany.

Purpose: Identification of molecular characteristics that are useful to define subgroups of patients fitting into differential treatment schemes is considered a most promising approach in cancer research. In this first study of such type, we therefore investigated the potential of multiplexed sandwich immunoassays to define protein expression profiles indicative of clinically relevant properties of malignant tumors.

Experimental Design: Lysates prepared from large core needle biopsies of 113 invasive breast carcinomas were analyzed with bead-based miniaturized sandwich immunoassays specific for 54 preselected proteins.

Results: Five protein concentrations [fibroblast growth factor-2 (FGF-2), Fas, Fas ligand, tissue inhibitor of metalloproteinase-1, and RANTES] were significantly different in the groups of patients with or without axillary lymph node metastasis. All 15 protein parameters that resulted in P values <0.2 and other diagnostic information [estrogen receptor (ER) status, tumor size, and histologic grading] were analyzed together by multivariate logistic regression. This yielded sets of five (FGF-2, Fas, Fas ligand, IP10, and PDGF-AB/BB) or six (ER staining intensity, FGF-2, Fas ligand, matrix metalloproteinase-13, PDGF-AB/BB, and IP10) parameters for which receiver-operator characteristic analyses revealed high sensitivities and specificities [area under curve (AUC) = 0.75 and AUC = 0.83] to predict the nodal status. A similar analysis including all identified parameters of potential value (15 proteins, ER staining intensity, T) without selection resulted in a receiver-operator characteristic curve with an AUC of 0.87.

Conclusion: We clearly showed that this approach can be used to quantify numerous proteins from breast biopsies accurately in parallel and define sets of proteins whose combined analyses allow the prediction of nodal involvement with high specificity and sensitivity.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4802DOI Listing
June 2008

Increased radiosensitivity as an indicator of genes conferring breast cancer susceptibility.

Strahlenther Onkol 2007 Dec;183(12):655-60

Department of Gynecology and Obstetrics, University of Ulm Medical School, Ulm, Germany.

Purpose: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity.

Material And Methods: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17.

Results: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045).

Conclusion: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness.
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http://dx.doi.org/10.1007/s00066-007-1774-2DOI Listing
December 2007

Stage IB endometrial cancer. Does lymphadenectomy replace adjuvant radiotherapy?

Strahlenther Onkol 2007 Nov;183(11):600-4

Department of Radiotherapy and Radiation Oncology, University Hospital, Ulm, Germany.

Background: The role of surgical lymph node dissection and adjuvant radiation therapy (RT) in early stage endometrial cancer is no longer clearly defined. The increased appreciation of lymphadenectomy and the absence of survival advantage from adjuvant RT rise controversies how patients should adequately be treated in stage IB endometrial cancer. The aim of this review is to rule out the validity of either treatment option and determine which preference provides the best therapeutic benefit.

Methods: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed.

Results: Based on the available data in the literature, for stage IB grade 1 or 2, the risk of pelvic relapse is considered too low to justify pelvic RT. However, intravaginal RT (IVRT) should be recommended for those >or= 60 years old or with lymphovascular invasion (LVI). For patients with stage IB grade 3 (and IC all grades), the treatment recommendation is mainly based on whether surgical lymph node staging was performed. These patients have--without surgical lymph node staging--a high risk of pelvic recurrence and should therefore primarily undergo relaparotomy for lymphadenectomy or pelvic RT as second choice. If these patients had a surgical lymph node staging, then IVRT alone is a reasonable alternative to pelvic RT.

Conclusion: Overall survival may not be the only ideal endpoint for stage IB endometrial cancer since causes of death are mostly other than endometrial cancer. Conventional pelvic RT may be overtreatment in some patients, in particular in those patients with a large number of negative lymph nodes after lymphadenectomy. However, negative surgical staging should not be understood as adjuvant RT can be omitted in all patients.
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http://dx.doi.org/10.1007/s00066-007-1801-3DOI Listing
November 2007

CD9 promotes adeno-associated virus type 2 infection of mammary carcinoma cells with low cell surface expression of heparan sulphate proteoglycans.

Int J Mol Med 2007 Feb;19(2):325-33

Department of Obstetrics and Gynaecology, University of Ulm Medical School, Frauensteige 14, D-89075 Ulm, Germany.

Recombinant adeno-associated virus (AAV) is a promising non-pathogenic vector in the emerging field of gene therapy. For AAV serotype 2 (AAV-2) infection, experimental evidence points to an involvement of heparan sulphate proteoglycans (HSPG), but also to the existence of additional receptors. We investigated a potential role of the tetraspanin CD9 in AAV-2 infection of breast cancer cells mainly because it binds to the heparin-binding EGF-like growth factor, suggesting that it may also interact with a heparin-binding virus. Among breast cancer cell lines, expression of HSPG or potential AAV-2 (co)-receptors was not found to correlate with transduction efficiency. In complete accordance with the role of CD9, blocking with anti-CD9 antibodies resulted in drastically decreased AAV-2 transduction efficiencies in cell lines with low expression of HSPG. Furthermore, specific inhibition of CD9 expression with siRNA resulted in fewer transgene-positive cells, whereas overexpression of CD9 in the breast cancer cell line T47D as well as in BT8Ca and BT12Ca rat glioma cells (with low background expression of HSPG and CD9) increased the number of AAV-transduced cells. The minimal epitope recognized by antibody 72F6, which most efficiently blocked AAV-mediated transgene expression, was deduced from the specific binding to peptides immobilized on colour-encoded microspheres consisting of the amino acid sequence PKKDV located in the large extracellular loop of CD9. Our results clearly point to an involvement of CD9 in the attachment, uptake or processing of AAV-2 by target cells expressing low amounts of HSPG, which may help to define cell populations accessible in AAV-based therapeutic applications.
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February 2007

Chemotherapeutic agents enhance AAV2-mediated gene transfer into breast cancer cells promoting CD40 ligand-based immunotherapy.

J Cancer Res Clin Oncol 2006 Dec 23;132(12):787-94. Epub 2006 Jun 23.

Department of Obstetrics and Gynecology, University of Ulm Medical School, Frauensteige 14, 89075, Ulm, Germany.

Purpose: Supplementing conventional treatment with gene therapy to induce an immune response might be beneficial to cancer patients. In this study, we evaluated the efficiency of transduction of breast cancer cells with recombinant adeno-associated virus (rAAV) and effects of cytotoxic agents used in chemotherapy. Furthermore, the capacity of tumor cells expressing transgenic CD40 ligand (CD40L) to stimulate dendritic cells was measured.

Methods: Breast cancer cell lines were infected with a rAAV encoding the enhanced green fluorescent protein (EGFP) or murine CD40L and transgene expression was analyzed by flow cytometry. Stimulation of isolated human dendritic cells by CD40L-expressing tumor cells was quantified by measuring secreted interleukin 12.

Results: Infection with an EGFP-encoding rAAV resulted in variable fractions (14-93%, mean 42%) of transgene-expressing cells. Pre-incubation of MM 157, MM 231, and MCF7 cells with epirubicin or carboplatin substantially increased AAV-mediated transgene expression. rAAV/CD40L was used to generate CD40L-transgenic tumor cells, which specifically activated immature dendritic cells, as confirmed by blocking with an antibody binding to CD40L.

Conclusions: The efficiency of rAAV-mediated gene transfer into breast cancer cells is significantly higher than previously reported and can be further enhanced by co-administration of chemotherapeutic agents. We also confirmed that breast cancer cells can activate human dendritic cells after infection with a CD40L-encoding rAAV.
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http://dx.doi.org/10.1007/s00432-006-0127-3DOI Listing
December 2006

Molecular targets of ovarian carcinomas with acquired resistance to platinum/taxane chemotherapy.

Curr Cancer Drug Targets 2006 May;6(3):207-27

University of Ulm Medical School, Department of Obstetrics and Gynaecology, Germany.

Ovarian cancer of epithelial origin remains one of the most lethal malignancies despite response rates of more than 80% in first-line combination chemotherapy with platinum drugs and taxanes following surgery. Poor overall prognosis is mainly due to acquired resistance of the recurring tumor mass to initially used and other chemotherapeutic agents. Therefore, novel therapeutic approaches are based on concepts to prevent (improvement of tumor exposure to drugs) or circumvent drug resistance, e.g. with new drugs structurally related to the currently used cytotoxic agents, other types of cytotoxic substances, or with target-specific novel drugs interfering with signaling and apoptotic pathways. In addition, acquired molecular characteristics of drug resistant ovarian carcinoma cells can be defined by expression profiling at different stages of therapy and might be used as specific targets for tumor-suppressing drugs and prodrugs containing cytotoxic components. Revelation of mechanistic details of drug resistance also provides the basis for the development of therapies with novel or conventional antitumor drugs in combination with specific inhibitors able to re-establish chemosensitivity. In this review, we summarize novel approaches in the treatment of ovarian cancer progressed to drug resistant stages and focus on the discussion of recently reported experimental and early clinical results with potentially useful strategies to overcome or modulate acquired drug resistance.
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http://dx.doi.org/10.2174/156800906776842975DOI Listing
May 2006

Immunotherapy and cancer vaccines in the management of breast cancer.

Curr Pharm Des 2005 ;11(27):3475-83

Department of Gynaecology and Obstetrics, University of Ulm Medical School, Ulm, Germany.

Besides the traditional therapeutic options, treatment with antibodies specific for the receptor tyrosine kinase HER-2/neu has been established as a standard therapy in the clinical management of advanced breast cancer. Ongoing clinical studies focus on the improvement of application protocols in order to minimize side effects and evaluate the potential therapeutic benefit of anti-HER-2/neu antibodies in combination with conventional chemotherapy. Various similar strategies to target other tumour-associated antigens or proangiogenic factors with inhibitory antibodies are currently investigated in promising preclinical and clinical trials. In addition, research efforts are made to develop procedures to generate tumour-specific cellular immune responses in breast cancer patients. Therapeutic vaccination is, however, still at an early stage of development, despite encouraging results of animal studies. We summarise and discuss vaccination strategies with tumour-specific proteins or peptides, pulsed dendritic cells, and modified tumour cells as well as antibody-based therapeutic concepts to target HER-2/neu, EGF receptor, MUC-1, uPA/uPAR, and VEGF.
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http://dx.doi.org/10.2174/138161205774414547DOI Listing
January 2006

Partial breast irradiation after breast-conserving surgery.

Strahlenther Onkol 2005 Jan;181(1):1-8

Department of Gynecology, University of Ulm, Germany.

Background: The standard technique of postoperative radiotherapy after breast-conserving surgery is percutaneous irradiation of the entire breast to a total dose of 45-50 Gy which is usually followed by a tumor bed boost. Since the majority of local recurrences in selected patients occur close to the former tumor bed, the question arises whether a sole tumor bed irradiation might be a therapeutic alternative to total breast irradiation.

Methods: A systematic review of relevant literature concerning partial breast irradiation (PBI) up to November 2004 was undertaken. Studies of any design were included for comparison and discussion.

Results: Nine unique brachytherapy studies using the multi-catheter technique, one the balloon technique (MammoSite), and eight particular intraoperative radiotherapy (IORT) trials were located of which only one was a randomized trial. Only minor postoperative complications were reported. Preliminary results are similar in terms of local tumor control, disease-free and overall survival. However, the current evidence base of IORT studies is poor.

Conclusion: Despite controversies regarding PBI after breast-conserving surgery, results of phase I-II trials suggest that sole tumor bed irradiation might be an appropriate therapeutic alternative for selected breast cancer patients. However, more experience and data from ongoing phase III trials are required to define these new methods to be an appropriate treatment option. Therefore, total breast irradiation still remains the standard irradiation modality even in the treatment of early breast cancer, and PBI should be considered investigational.
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http://dx.doi.org/10.1007/s00066-005-1394-7DOI Listing
January 2005

Protein Microarrays - A Promising Tool for Cancer Diagnosis.

Cancer Genomics Proteomics 2005 Jan-Feb;2(1):37-42. Epub 2005 Jan 1.

NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstraße 55, 72770 Reutlingen, Germany

Within recent years, protein microarrays have been developed to quantify a large number of parameters present in a given sample simultaneously. Such miniaturised and parallelised sandwich immunoassays are of general interest for all proteomic and diagnostic approaches in which several parameters have to be determined from small samples, e.g. biopsy material. In addition to planar microarray-based approaches, bead-based flow cytometry is quite suitable for the multiplex detection of target molecules, especially when a limited number of parameters are to be analysed. Appropriate sensitivity, reproducibility and robustness have to be demonstrated before protein microarray technology can be used to characterise clinical samples and generate reliable data sets. As a model system to analyse these issues, a set of multiplexed sandwich immunoassays based on Luminex beads were developed to screen clinical samples for the presence or absence of marker proteins indicative of prognosis or response to therapeutic options.
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January 2005

Efficient gene transfer of CD40 ligand into ovarian carcinoma cells with a recombinant adeno-associated virus vector.

Int J Oncol 2005 Jan;26(1):95-101

University of Ulm Medical School, Department of Obstetrics and Gynecology, Ulm, Germany.

Recombinant adeno-associated virus type 2 (rAAV) has many properties of an ideal vector for gene therapy: broad spectrum of susceptible cells, efficient gene transfer, persistent transgene expression in vivo, and no indiction of vector-related toxicity. Ovarian carcinoma cell lines, however, were previously reported to be quite resistant to rAAV transduction. Using an optimized adenovirus-free packaging system, highly purified rAAV vectors coding for the enhanced green fluorescent protein (AAV/EGFP) and for mCD40 ligand (AAV/CD40L) were generated. Their transduction efficiency in ovarian carcinoma cell lines was assessed with and without irradiation prior to infection. As measured by flow cytometry, transgene expression in up to 92% of cells was achieved with AAV/EGFP. gamma-irradiation (20 Gy) significantly increased the transduction rates up to 3.5-fold in cell lines with low susceptibility to AAV infection. The aquired capability of AAV/CD40L transduced tumor cells to activate dendritic cells was demonstrated in a second step. Dendritic cells were generated from human peripheral blood monocytes and maturized by stimulation with IL-4 and GM-CSF. Co-cultivation of mCD40L transgenic tumor cells with these dendritic cells resulted in strong ELISA-determined expression of IL-12 as an indicator of dendritic cell activation. We conclude that transduction of tumor cells with rAAV encoding mCD40L is a promising strategy for tumor immunotherapy which may be further developed to a vaccination approach with transgenic ovarian carcinoma cells generated by ex vivo transduction.
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January 2005

Spectrum of p53 mutations in biopsies from breast cancer patients selected for preoperative chemotherapy analysed by the functional yeast assay to predict therapeutic response.

Oncol Rep 2004 Jun;11(6):1281-6

Department of Obstetrics and Gynecology, University of Ulm Medical School, D-89075 Ulm, Germany.

The most frequent alteration detected in breast cancer cells is an inactivation of the tumor protein p53. Numerous studies revealed that p53 mutations are an independent prognostic indicator of a shorter period of overall and disease-free survival. Meta-analysis of these investigations clearly showed that prognostic significance cannot be achieved by indirect assessment of the p53 status by immunohistochemistry. Therefore, the tumor RNA-based functional p53 assay in yeast (functional assay of separated alleles in yeast, FASAY) appears to be an attractive option to generate clinically relevant information without the need of microdissection. We describe FASAY analyses of 50 biopsies taken before pre-operative anthracycline/taxane chemotherapy to evaluate the predictive value of p53 mutations for this common combination of substances. Wild-type p53, present in 22 samples, resulted in numerous white colonies with a low background of red colonies that was consistently below 8%. Biopsy samples containing mutated alleles gave rise to many red colonies accompanied with variable numbers of white colonies. With one single exception, all biopsies containing mutated p53 resulted in more than 8% red colonies. In 25 samples (53%), 23 single and 2 double mutations of the p53 gene were confirmed by sequencing of DNA from the yeast colonies. Six of the observed sequence insertions or deletions and 2 of the point mutations have not been reported previously. In accordance with an abolished or altered function as a transcriptional activator, most mutations affected the p53 DNA-binding domain, and one the tetramerization domain. Our results confirmed that the FASAY is sufficiently reliable to detect p53 mutations in breast tumor biopsies. In this pilot study with a limited number of patients to evaluate the predictive value of p53 mutations for an anthracycline/taxane combination therapy in the neoadjuvant setting, stable disease was observed more often in patients with wild-type p53 but statistical significance was not quite reached for this clear trend.
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June 2004

Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion.

Clin Cancer Res 2003 Dec;9(17):6426-31

Department of Obstetrics and Gynecology, University of Ulm Medical School, Ulm, Germany.

Purpose And Experimental Design: Lymphovascular space invasion plays a critical role in the progression of cervical cancer and is an indicator of an unfavorable prognosis, even in patients with early-stage disease. Identification and functional characterization of molecules that are predominantly expressed in tumors able to penetrate lymphatic vessels may therefore help to improve the clinical assessment of cervical neoplasias with unclear prognosis. We used immunohistochemical staining to assess expression of the tetraspanin adapter protein CD9 in cervical tumors because inverse correlations with tumor invasiveness, ability to form metastases, and poor clinical outcome have been described for several other tumor types.

Results And Conclusion: We found that CD9, strongly expressed by cells forming the basal layer of normal squamous epithelium of the cervix, is down-regulated in most invasive cervical carcinomas (correlation with stage, P = 0.015) but apparently re-expressed at distinct regions during tumor progression. Tumor sites with pronounced localized expression of CD9 (CD9 hotspots) include cones growing into blood or lymphatic vessels, pointing to a functional role of CD9 in transendothelial migration as a crucial step in the formation of lymph node metastases. Remarkably, CD9 hotspots were found to be a highly significant (P < 10(-5)) indicator of lymphangiosis: they were observed in 15 of 18 cases with histopathologically confirmed lymphangiosis compared with 4 of 26 other cervical carcinomas. We postulate, therefore, that clusters of tumor cells characterized by strong expression of CD9 may be useful as an indicator of high risk of recurrence in early-stage cervical cancer, providing a basis for clinical decisions in favor of additional treatment.
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December 2003

Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer.

Int J Oncol 2003 May;22(5):1117-21

Department of Obstetrics and Gynecology, University of Ulm Medical School, Ulm, Germany.

P-glycoprotein, encoded by the MDR-1 gene, confers multi-drug resistance against antineoplastic agents and is important for the transmembrane transition of various other common therapeutic drugs. Recently, a number of polymorphisms in the MDR-1 gene were identified and the T/T genotype at position 3435 in exon 26 was found to correlate with intestinal P-glycoprotein expression and bioavailability of digoxin after oral administration. We analysed the allelic frequencies at the polymorphic site C3435T in a group of patients with locally advanced breast cancer treated by preoperative chemotherapy to evaluate its predictive value. Sixty-eight patients diagnosed between 1998 and 2001 were treated by preoperative chemotherapy with anthracyclines or these agents combined with taxanes. From genomic DNA, a 106 bp fragment of MDR-1 exon 26 was amplified and the C3435T genotype was determined by Pyrosequencing methodology. A potential correlation with therapeutic response was calculated with Fisher's exact test. The overall clinical response rate (cCR and cPR) was 68% but only 7 patients (10.3%) achieved pathological complete response (pCR). Heterozygous C3435T occurred in 57% of the subjects and 22% of the analysed individuals possessed only T alleles. Statistical analysis revealed a significant correlation (p=0.029) between clinical complete response to preoperative chemotherapy and the T/T genotype. MDR-1 polymorphism C3435T in exon 26 may co-determine resistance to chemotherapy and provide useful information to individualize therapy.
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May 2003

Expression of tetraspanin adaptor proteins below defined threshold values is associated with in vitro invasiveness of mammary carcinoma cells.

Oncol Rep 2003 Mar-Apr;10(2):405-10

Department of Obstetrics and Gynecology, University of Ulm Medical School, Ulm, Germany.

Tetraspanins are transmembrane adaptor proteins involved in the regulation of various fundamental cellular processes. For a number of malignant diseases, the level of expression of members of the tetraspanin family was found to correlate with tumor cell invasiveness, ability to form metastases, and poor clinical outcome. We describe the exact quantification of mRNAs coding for the tetraspanins CD9, CD63, CD82 and CD151 expressed by mammary carcinoma-derived cell lines that were classified as invasive or non-invasive according to their ability to penetrate collagen-fibroblast gels in vitro. The mean of beta2-microglobulin-normalized expression of CD9 was about 10-fold higher than the mean calculated for CD63 and about 20-fold higher than expression of CD82 and CD151. Direct comparison of tetraspanin expression of invasive and non-invasive cell lines with the Mann-Whitney test revealed a significant correlation for CD63. Grouping of cell lines in relation to threshold values of expression resulted in significant correlations for CD63 (Fisher's exact test p=0.004) and CD151 (p=0.02) but not for CD82 (p=0.065) and CD9 (p=0.168). Expression of CD9, C63 and CD151 was found to be coupled whereas CD82 was expressed independently. This highly significant association points to common mechanisms of gene regulation for this subgroup of tetraspanins. We showed that on basis of absolute amounts of tetraspanin mRNAs, at least in vitro invasiveness is clearly predictable. Our results support the assumption that downregulation of tetraspanins in breast cancer cells is an important step of tumor progression to more malignant phenotypes and underline their important role as mediators in multimolecular membrane protein complexes regulating cell adhesion and migration.
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July 2003

Angiogenesis: prognostic and therapeutic implications in gynecologic and breast malignancies.

Curr Opin Obstet Gynecol 2003 Feb;15(1):45-9

Department of Gynecology and Obstetrics, University of Ulm Medical School, Germany.

Purpose Of Review: Growth, invasion and metastasis of malignant tumors depend on angiogenesis, which is therefore considered an attractive therapeutic target and indicator of clinical outcome. Summarizing the results of very recent studies, we discuss the clinical relevance of vascularization of breast and gynecological tumors.

Recent Findings: The prognostic values of directly assessed vascularity (microvessel density) and angiogenic factors have been confirmed for these malignancies, despite few contradictory results that may be due to methodological inaccuracy. In addition, many studies point to a role of angiogenesis as a predictor of response to both antiangiogenic and conventional chemotherapy or radiotherapy. For a conclusive evaluation, however, further studies covering all clinically relevant subgroups of patients are needed. Novel therapeutic approaches with inhibitors of angiogenesis are promising, although the adaptation of most experimentally proven approaches to clinical practice appears to be a laborious process. Furthermore, for an appropriate clinical evaluation of these drugs, newly defined endpoints of treatment and new monitoring systems reflecting their mode of action and the anticipated biological effects are required.

Summary: The prognostic and predictive value of angiogenic factors and microvessel density has been confirmed. Antiangiogenic therapy will most likely play an important role in future clinical management of malignant diseases.
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http://dx.doi.org/10.1097/00001703-200302000-00007DOI Listing
February 2003

Basal expression of the multidrug resistance gene 1 (MDR-1) is associated with the TT genotype at the polymorphic site C3435T in mammary and ovarian carcinoma cell lines.

Cancer Lett 2002 Nov;185(1):79-85

Department of Obstretrics and Gynecology, University of Ulm Medical School, Frauensteige 14, D-89075, Ulm, Germany.

Resistance to established drugs for cancer therapy is in many cases associated with overexpression of the multidrug resistance gene 1 (MDR-1). Regulation of basal expression of MDR-1 and mechanisms of induction as a result of exposure to cytotoxic substances are still not completely understood. Recent reports have suggested an association of the C3435T polymorphism in exon 26 of the MDR-1 gene with MDR-1 expression in duodenal mucosa cells of healthy individuals. We analyzed the C3435T and G2677T genotypes of 38 mammary and ovarian carcinoma cell lines and measured basal MDR-1 expression by real-time reverse transcriptase-polymerase chain reaction. Cell lines were classified as non-expressing or showing weak basal expression that was found to be significantly associated (six/seven versus 13/31 expressing cell lines; P=0.0448, Fisher's exact test) with the TT genotype at position 3435 of the MDR-1 gene.
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http://dx.doi.org/10.1016/s0304-3835(02)00232-xDOI Listing
November 2002

New molecular targets of breast cancer therapy.

Strahlenther Onkol 2002 Mar;178(3):123-33

Department of Gynecology and Obstetrics, University of Ulm Medical School, Ulm, Germany.

Background: The development of new chemotherapeutic agents and concepts of radiation therapy, administered as primary, adjuvant and palliative therapy, has led to new perspectives in breast cancer therapy. Apart from conventional chemotherapy, recently developed novel agents interfere with molecular mechanisms that are altered in cancer cells. Those targets are not necessarily breast cancer-specific. In this review we will focus on novel agents with potential or already proved benefit to breast cancer patients. Promising strategies include inhibition of growth factor receptors, blocking of tumor angiogenesis and signal transduction pathways, modulation of apoptosis, cancer vaccination, and inhibition of invasion and metastasis.

Methods: Reports of relevant studies obtained from a search of MEDLINE and studies referenced in those reports were reviewed.

Results: Apart from trastuzumab, other further developed compounds show promising results in clinical studies as a second generation of growth factor inhibitors. Different approaches in anti-angiogenetic therapy are under preclinical and clinical phase-II trials. Pro-apoptotic agents show synergistic effects with docetaxel in a clinical phase-I trial. Other compounds that target HSP 90, histone deacetylase and HMG-CoA reductase target atypical apoptotic pathways being lethal to tumor cells only but not to normal tissue, suggesting a tumor-specific way of action. MMP inhibitors have been demonstrating promising results in patients with refractory malignant pleural effusion in a phase-I trial. Several tyrosine kinase inhibitors currently under clinical investigation preliminarily show hopeful results in patients with advanced breast cancer. Furthermore, recent progress in defining the immunogenic epitopes of tumor antigens has rejuvenated the interest in cancer vaccines.

Conclusion: Typical dose escalation studies leading to the highest clinically still tolerated dose do not appear to be equally appropriate for the estimation of efficiency of those compounds as for conventional cytotoxic regimes. Rather, escalation up to an amount of therapeutic agent that is sufficient for maximum target inhibition should be promoted, where classical measures of cytoreduction such as complete or partial remission are replaced both by time to progression and treatment failure as an appropriate measure of the efficacy of an agent.
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http://dx.doi.org/10.1007/s00066-002-0957-0DOI Listing
March 2002
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