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Featured researches published by Stephan Braun.


The New England Journal of Medicine | 2000

Cytokeratin-Positive Cells in the Bone Marrow and Survival of Patients with Stage I, II, or III Breast Cancer

Stephan Braun; Klaus Pantel; Peter Müller; Wolfgang Janni; Florian Hepp; Christina Kentenich; Stephan Gastroph; Artur Wischnik; Thomas Dimpfl; Günter Kindermann; Gert Riethmüller; Günter Schlimok

BACKGROUNDnCytokeratins are specific markers of epithelial cancer cells in bone marrow. We assessed the influence of cytokeratin-positive micrometastases in the bone marrow on the prognosis of women with breast cancer.nnnMETHODSnWe obtained bone marrow aspirates from both upper iliac crests of 552 patients with stage I, II, or III breast cancer who underwent complete resection of the tumor and 191 patients with nonmalignant disease. The specimens were stained with the monoclonal antibody A45-B/B3, which binds to an antigen on cytokeratins. The median follow-up was 38 months (range, 10 to 70). The primary end point was survival.nnnRESULTSnCytokeratin-positive cells were detected in the bone marrow specimens of 2 of the 191 control patients with nonmalignant conditions (1 percent) and 199 of the 552 patients with breast cancer (36 percent). The presence of occult metastatic cells in bone marrow was unrelated to the presence or absence of lymph-node metastasis (P=0.13). After four years of follow-up, the presence of micrometastases in bone marrow was associated with the occurrence of clinically overt distant metastasis and death from cancer-related causes (P<0.001), but not with locoregional relapse (P=0.77). Of 199 patients with occult metastatic cells, 49 died of cancer, whereas of 353 patients without such cells, 22 died of cancer-related causes (P<0.001). Among the 301 women without lymph-node metastases, 14 of the 100 with bone marrow micrometastases died of cancer-related causes, as did 2 of the 201 without bone marrow micrometastases (P<0.001). The presence of occult metastatic cells in bone marrow, as compared with their absence, was an independent prognostic indicator of the risk of death from cancer (relative risk, 4.17; 95 percent confidence interval, 2.51 to 6.94; P<0.001), after adjustment for the use of systemic adjuvant chemotherapy.nnnCONCLUSIONSnThe presence of occult cytokeratin-positive metastatic cells in bone marrow increases the risk of relapse in patients with stage I, II, or III breast cancer.


Journal of Clinical Oncology | 2000

Lack of Effect of Adjuvant Chemotherapy on the Elimination of Single Dormant Tumor Cells in Bone Marrow of High-Risk Breast Cancer Patients

Stephan Braun; Christina Kentenich; Wolfgang Janni; Florian Hepp; Johann de Waal; F. Willgeroth; H. Sommer; Klaus Pantel

PURPOSEnThere is an urgent need for markers that can predict the efficacy of adjuvant chemotherapy in patients with solid tumors. This study was designed to evaluate whether monitoring of micrometastases in bone marrow can predict the response to systemic chemotherapy in breast cancer.nnnPATIENTS AND METHODSnBone marrow aspirates of 59 newly diagnosed breast cancer patients with either inflammatory (n = 23) or advanced (> four nodes involved) disease (n = 36) were examined immunocytochemically with the monoclonal anticytokeratin (CK) antibody A45-B/B3 (murine immunoglobulin G(1); Micromet, Munich, Germany) before and after chemotherapy with taxanes and anthracyclines.nnnRESULTSnOf 59 patients, 29 (49.2%) and 26 (44.1%) presented with CK-positive tumor cells in bone marrow before and after chemotherapy, respectively. After chemotherapy, less than half of the previously CK-positive patients (14 of 29 patients; 48.3%) had a CK-negative bone marrow finding, and 11 (36. 7%) of 30 previously CK-negative patients were CK-positive. At a median follow-up of 19 months (range, 6 to 39 months), Kaplan-Meier analysis of 55 assessable patients revealed a significantly reduced overall survival (P =.011; log-rank test) if CK-positive cells were detected after chemotherapy. In multivariate analysis, the presence of CK-positive tumor cells in bone marrow after chemotherapy was an independent predictor for reduced overall survival (relative risk = 5.0; P =.016).nnnCONCLUSIONnThe cytotoxic agents currently used for chemotherapy in high-risk breast cancer patients do not completely eliminate CK-positive tumor cells in bone marrow. The presence of these tumor cells after chemotherapy is associated with poor prognosis. Thus, bone marrow monitoring might help predict the response to systemic chemotherapy.


Cancer | 2006

A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation

Tanja Fehm; Stephan Braun; Volkmar Müller; Wolfgang Janni; Gerhard Gebauer; Christian Marth; Christian Schindlbeck; Diethelm Wallwiener; Elin Borgen; Bjørn Naume; Klaus Pantel; Erich Solomayer

Numerous single‐institutional studies and a large pooled analysis have demonstrated that the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) from patients with primary, nonmetastatic breast cancer (Stages I‐III) is associated with impaired prognosis. To date, sampling of BM and assessment of DTCs is not considered a routine procedure in the clinical management of breast cancer patients; however, emerging data suggest a future role for risk stratification and monitoring of therapeutic efficacy. Because these clinical options need to be evaluated in trials to verify the principle of this concept in the clinical setting, agreement on the standardized detection of DTCs is necessary. Consequently, the German, Austrian, and Swiss Societies for Senology recently formed a panel 1) to review and discuss the existing methodologies, 2) to find a consensus for a standardized detection of DTCs, and 3) to explore the options for its clinical implementation. Cancer 2006.


Journal of Clinical Oncology | 2001

Comparative Analysis of Micrometastasis to the Bone Marrow and Lymph Nodes of Node-Negative Breast Cancer Patients Receiving No Adjuvant Therapy

Stephan Braun; B. Semeni Cevatli; Cyamak Assemi; Wolfgang Janni; Christina Kentenich; Christian Schindlbeck; D. Rjosk; Florian Hepp

PURPOSEnIn node-negative patients, of whom up to 30% will recur within 5 years after diagnosis, markers are still needed that identify patients at high enough risk to warrant further adjuvant treatment. In the present study we analyzed whether a correlation exists between microscopic tumor cell spread to bone marrow and to lymph nodes and attempted to determine which route is clinically more important.nnnPATIENTS AND METHODSnAccording to a prospective design, bone marrow aspirates and axillary lymph nodes of level I (n = 1,590) from 150 node-negative patients with stage I or II breast cancer were analyzed immunocytochemically with monoclonal anticytokeratin (CK) antibodies. We investigated associations with prognostic factors and the effect of micrometastasis on patients prognosis.nnnRESULTSnCK-positive cells in bone marrow aspirates were present in 44 (29%) of 150 breast cancer patients, whereas only 13 patients (9%) had such positive findings in lymph nodes; simultaneous microdissemination to bone marrow and lymph nodes was seen in merely two patients. No correlation of bone marrow micrometastases with other risk factors was assessed. Reduced 4-year distant disease-free and overall survival were each associated with a positive bone marrow finding (P =.032 and P =.014, respectively) but not with lymph node micrometastasis. Multivariate analysis revealed an independent prognostic effect of bone marrow micrometastasis on survival, with a hazards ratio of 6.1 (95% confidence interval, 1.2 to 31.3) for cancer-related death (P =.031) in our series.nnnCONCLUSIONnImmunocytochemical detection of micrometastatic cells in bone marrow but not in lymph nodes is an independent prognostic risk factor in node-negative breast cancer that may have implications for surgery and stratification into adjuvant therapy trials.


Clinical Cancer Research | 2011

Persistence of Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients Predicts Increased Risk for Relapse—A European Pooled Analysis

Wolfgang Janni; Florian D. Vogl; Marit Synnestvedt; Tanja Fehm; Julia Jückstock; Elin Borgen; Brigitte Rack; Stephan Braun; H. Sommer; Erich Solomayer; Klaus Pantel; Jahn M. Nesland; Klaus Friese; Bjørn Naume

Background: The prognostic significance of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTCs after adjuvant therapy increases the risk of subsequent relapse and death. Patients and Methods: Individual patient data from 676 women with primary diagnosis of early breast cancer stages I–III from 3 follow-up studies were pooled. During clinical follow-up, patients underwent BM aspiration (BMA) to determine the presence of DTC. Tumor cells were detected by the standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS). Results: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for DFS, distant DFS (DDFS), cancer-specific survival, and OS during the first 5 years following cancer diagnosis (log-rank test P < 0.001 values for all investigated endpoints). Conclusion: Among breast cancer patients, persistent DTCs during follow-up significantly predicted the increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials. Clin Cancer Res; 17(9); 2967–76. ©2011 AACR.


Journal of Clinical Oncology | 2001

Occult Tumor Cells in Bone Marrow of Patients With Locoregionally Restricted Ovarian Cancer Predict Early Distant Metastatic Relapse

Stephan Braun; Christian Schindlbeck; Florian Hepp; Wolfgang Janni; Christina Kentenich; Gert Riethmüller; Klaus Pantel

PURPOSEnBased on conventional tumor staging, primary ovarian cancer is viewed as an intraperitoneal disease that rarely spreads to extraperitoneal organs. However, autopsy studies reveal a much higher rate of occult metastasis, indicating that extraperitoneal spread occurs with much greater frequency than previously appreciated. Consequently, we investigated the incidence of early hematogenous dissemination and its association with distant disease-free and overall survival.nnnPATIENTS AND METHODSnBone marrow aspirates from 108 patients newly diagnosed with International Federation of Gynecology and Obstetrics stage I to III ovarian cancer were prospectively analyzed with the novel anti-cytokeratin (CK) antibody A45-B/B3. We investigated the frequency of CK-positive tumor cells in bone marrow and their effect on prognosis in relation to established risk factors for tumor progression.nnnRESULTSnTumor cells in bone marrow were detected in 32 (30%) of 108 patients. A CK-positive finding was unrelated to established risk parameters, except for poor nuclear grading of the primary tumor. At a median follow-up of 45 months (range, 12 to 77 months), the presence of occult metastatic cells in bone marrow was associated with the occurrence of clinically overt, extraperitoneal (predominantly extraskeletal) distant metastasis (relative risk [RR], 16.5; 95% confidence interval [CI], 6.2 to 56.9; P < .0001) and death from cancer-related causes (RR, 2.3; 95% CI, 1.2 to 4.3; P = .01). Multivariate analysis identified a positive bone marrow finding as an independent prognostic factor of reduced distant disease-free survival for all patients (RR, 13.8; 95% CI, 5.4 to 52.9; P < .0001) and for the 64 stage R0-1 patients (RR, 7.3; 95% CI, 1.5 to 56.8; P = .0021).nnnCONCLUSIONnOur data signal that hematogenous dissemination of tumor cells occurs early and throughout all stages of ovarian cancer. The clinical significance of our findings is supported by the unfavorable prognosis in association with the presence of occult metastatic cells, especially in those patients who received an effective locoregional therapy.


Cancer | 2000

Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma

Wolfgang Janni; Stephan Gastroph; Florian Hepp; Christina Kentenich; D. Rjosk; Christian Schindlbeck; Thomas Dimpfl; H. Sommer; Stephan Braun

Using cytokeratin (CK) as a histogenetic marker of epithelial tumor cells in the bone marrow of patients with primary breast carcinoma, a subgroup of patients with decreased survival can be identified. This study was designed to evaluate the frequency and prognostic relevance of such cells in patients with recurrent breast carcinoma.


JAMA | 2010

Circulating tumor cells revisited.

Massimo Cristofanilli; Stephan Braun

DESPITE THE USE OF MODERN HIGH-RESOLUTION imaging technologies, it is not possible to detect tumor cell metastasis at a single cell level. To date, cancer treatment is initiated only after the clinical presentation of disease. This approach generally is unsuccessful and translates into the dogma that metastasis is a terminal process, generally viewed as fatal. Recent advances showing prolongation of survival in some tumor types and mitigation of clinical symptoms have stimulated both translational and clinical research to detect and characterize micrometastatic disease in the form of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs), both of which are considered to be early accessible cellular determinants of subsequent overt metastasis. In this Commentary, we describe recent advances in CTC research, which raise the possibility that treatments with curative intent might be applied successfully to patients with micrometastatic cancer (ie, evidence of disease on a cellular level), thereby potentially preventing subsequent fatal metastatic disease. The first documented research on tumor cells in the peripheral blood circulation was reported in 1869 by Ashworth. Since then, the existence, origin, and clinical significance of CTCs have increasingly attracted investigators’ interest. However, realization of the potential application of CTC is only beginning because the main limitation for its clinical consideration has been the need for development and robust validation of CTC enrichment and detection technologies. This technique relies on detection and quantification of extremely low numbers of CTCs. Most procedures involve immunomagnetic bead separation and using tumor cell antigens (eg, epithelial cell adhesion molecule [EpCAM]) or hematopoietic cell antigens (eg, common leukocyte antigen [CD45]) for purified cell suspensions, followed by conventional immunostaining for typing epithelial origin. Currently, only 1 standardized and validated assay has been approved by the US Food and Drug Administration. With this assay, a small peripheral blood sample is exposed to ferrofluid-coated antibodies directed against the EpCAM to extract EpCAM-positive cells through a magnetic field. For subsequent computer-generated (semiautomated fluorescence–based microscopy system) classification of immunostained cells as CTCs, the enriched EpCAM-positive cell fraction is validated image by image against the presence of epithelial-specific anticytokeratin staining, proper nucleus staining, and the absence of leukocyte-specific CD45 staining. Using this technology, CTCs have been investigated in several tumor types including breast, prostate, and colorectal cancers, and trials in breast cancer have documented the prognostic significance of CTCs. In a trial of 177 patients with metastatic breast cancer who were initiating systemic treatment, a cut point of 5 CTCs per 7.5 mL differentiated patients with higher CTC counts and both shorter progression-free and overall survival of 2.7 and 10.9 months, respectively, from patients classified below this threshold with 7.0 months progression-free survival (P=.0001) and 21.9 months overall survival (P .0001). In subsequent post hoc analyses, continued CTC monitoring provided more accurate prognostic information than high-resolution anatomical imaging of metastatic tumor burden and higher accuracy than functional imaging. In future trial settings, both CTC quantity and molecular features may provide information relevant for improved patient treatment as recently suggested for patients with advanced prostate cancer and metastatic colorectal cancer. Other technologies have been introduced in attempt to limit these technological shortcomings. A microfluidic chip technology was applied to samples from patients with non– small cell lung cancer, and demonstrated the feasibility for CTC monitoring and assessment of genetic marker– guided treatment effects. The method enabled interaction between CTCs and microposts coated with an antibody against EpCAM under precisely controlled laminar-flow conditions, thus aiming to reduce the level of false negativity due to cell loss during immunomagnetic separation processes, which appears to be achievable given the high CTC recovery rate. However, the limitation of this approach and most other investigational technologies is the requirement of antibody


Cancer Investigation | 2009

The Prognostic Impact of Bone Marrow Micrometastases in Women with Breast Cancer

Stephan Braun; Doris Auer; Christian Marth

Metastasis is the overwhelming cause of mortality in patients with breast cancer and our understanding of its cellular and molecular determinants is limited. Among cellular determinants, disseminated (DTC) tumor cells undoubtedly are key players in the metastatic cascade. In the past, several models have been constructed to explain the presence of individual tumor cells in secondary organs and their influence on the subsequent course of the disease. According to most recent transcriptome and genome analyses, DTCs are viewed as rare and much earlier indicators of metastasis than generally assumed from the typical course of breast cancer. Despite the observation that the numerous genetic alterations in such cells are rarely identical or even similar, characterization of the long interval between dissemination and clinically manifested metastases, the resistance to chemotherapy and significant effect on disease progression despite the low abundance in secondary organs, support the idea that some of these cells might be progenitor cells with self-renewing properties that give rise to most of the tumor mass that is dealt with clinically. Here, we review evidence from translational research and data from observational studies on DTCs to elucidate their potential impact for both future clinical trial design and, in the long run, decision-making in our daily patient management.


International Journal of Radiation Oncology Biology Physics | 2000

RADIOTHERAPY OF THE CHEST WALL FOLLOWING MASTECTOMY FOR EARLY-STAGE BREAST CANCER: IMPACT ON LOCAL RECURRENCE AND OVERALL SURVIVAL

Wolfgang Janni; Thomas Dimpfl; Stephan Braun; Angelika Knobbe; Ursula Peschers; D. Rjosk; Bjoern Lampe; Thomas Genz

INTRODUCTIONnRecent studies have renewed an old controversy about the efficacy of adjuvant radiotherapy following mastectomy for breast cancer. Radiotherapy is usually recommended for advanced disease, but whether or not to use it in pT1-T2 pN0 situations is still being debated. This study was designed to clarify whether or not routine radiotherapy of the chest wall following mastectomy reduces the risk of local recurrence and if it influences the overall survival rate.nnnMETHODSnRetrospective analysis of patients treated with mastectomy for pT1-T2 pN0 tumors and no systemic treatment. Patients treated with radiotherapy of the chest wall following mastectomy (Group A) are compared with those treated with mastectomy alone (Group B).nnnRESULTSnA total of 918 patients underwent mastectomy. Patients who received adjuvant radiotherapy after mastectomy (n = 114) had a significantly lower risk for local recurrence. Ten years after the primary diagnosis, 98.1% of the patients with radiotherapy were disease free compared to 86.4% of the patients without radiotherapy. The average time interval from primary diagnosis until local recurrence was 8.9 years in Group A and 2.8 years in Group B. The Cox regression analysis including radiotherapy, tumor size and tumor grading found the highest risk for local recurrence for patients without radiotherapy (p < 0.0004). In terms of overall survival however, the Kaplan-Meier analysis showed no difference between the two groups (p = 0.8787) and the Cox regression analysis failed to show any impact on overall survival.nnnCONCLUSIONnWith observation spanning over 35 years, this study shows that adjuvant radiotherapy of the chest wall following mastectomy reduces the risk for local recurrence in node-negative patients with pT1-T2 tumors but has no impact on the overall survival rate.

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Christian Marth

Innsbruck Medical University

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Bjørn Naume

Oslo University Hospital

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Alain G. Zeimet

Innsbruck Medical University

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Daniel Reimer

Innsbruck Medical University

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Doris Auer

Innsbruck Medical University

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