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  • 1
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    Clonal Heterogeneity in Growth Kinetics of CD34 + CD38 − Human Cord Blood Cells In Vitro Is Correlated with Gene Expression Pattern and Telomere Length
    Oxford University Press (OUP) ; 2005
    In:  STEM CELLS Vol. 23, No. 7 ( 2005-08), p. 946-957
    Details
    In: STEM CELLS, Oxford University Press (OUP), Vol. 23, No. 7 ( 2005-08), p. 946-957
    Type of Medium: Online Resource
    ISSN: 1066-5099 , 1549-4918
    URL: Article
    DOI: 10.1634/stemcells.2004-0311
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2005
    detail.hit.zdb_id: 2030643-X
    detail.hit.zdb_id: 1143556-2
    detail.hit.zdb_id: 605570-9
    SSG: 12
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  • 2
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    Detection and HER2 Expression of Circulating Tumor Cells: Prospective Monitoring in Breast Cancer Patients Treated in the Neoadjuvant GeparQuattro Trial
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 9 ( 2010-05-01), p. 2634-2645
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 9 ( 2010-05-01), p. 2634-2645
    Abstract: Purpose: This study was aimed at detecting and characterizing circulating tumor cells (CTC) before and after neoadjuvant therapy (NT) in the peripheral blood of patients with breast cancer. Experimental Design: The clinical trial GeparQuattro incorporated NT approaches (epirubicin/cyclophosphamide prior to randomization to docetaxel alone, docetaxel in combination with capecitabine, or docetaxel followed by capecitabine) and additional trastuzumab treatment for patients with HER2-positive tumors. We used the Food and Drug Administration–approved CellSearch system for CTC detection and evaluation of HER2 expression and developed HER2 immunoscoring for CTC. Results: We detected ≥1 CTC/7.5 mL in 46 of 213 patients (21.6%) before NT and in 22 of 207 patients (10.6%) after NT (P = 0.002). Twenty (15.0%) initially CTC-positive cases were CTC-negative after NT, whereas 11 (8.3%) cases were CTC-positive after NT, although no CTC could be found before NT. CTC detection did not correlate with primary tumor characteristics. Furthermore, there was no association between tumor response to NT and CTC detection. HER2-overexpressing CTC were observed in 14 of 58 CTC-positive patients (24.1%), including 8 patients with HER2-negative primary tumors and 3 patients after trastuzumab treatment. CTC scored HER2-negative or weakly HER2-positive before or after NT were present in 11 of 21 patients with HER2-positive primary tumors. HER2 overexpression on CTC was restricted to ductal carcinomas and associated with high tumor stage (P = 0.002). Conclusion: CTC number was low in patients with primary breast cancer. The decrease in CTC incidence during treatment was not correlated with standard clinical characteristics and primary tumor response. Information on the HER2 status of CTC might be helpful for stratification and monitoring of HER2-directed therapies. Clin Cancer Res; 16(9); 2634–45. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-2042
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Identification of Defects in the Transcriptional Program during Differentiation of CD34+Cells Selected from Patients with Both, Low- and High-Risk Myelodysplastic Syndromes.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 201-201
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 201-201
    Abstract: The development of MDS is suggested to follow a multistep pathogenesis and is characterized by accumulation of molecular defects of the hematopoietic stem/progenitor cells. To detect alterations within the transcriptional program in MDS derived CD34+ cells during lineage-specific differentiation, CD34+ bone marrow cells were selected from healthy individuals (n=3) and patients with low-risk (IPSS, n=3) or high-risk (n=4) MDS and stimulated in vitro with EPO, TPO or G/GM-CSF to induce lineage-specific differentiation. Lineage-determined cells were harvested and if necessary purified by immunomagnetic beads at days 4, 7 and 11 for gene expression profiling. Gene expression was analyzed by oligonucleotide microarrays (HG-U133A, Affymetrix, Santa Clara, CA). The experiments were done in triplicates for each of the time points and each of the conditions. First, we identified 260 genes with a significant expression pattern associated with normal lineage-specific differentiation. These continuously up- or down-regulated genes are considered to be part of a specific genetic program of normal hematopoietic cells during lineage-specific differentiation. In MDS, 57% of these genes showed a different expression from the normal transcriptional pattern. Thirteen of 24 genes up-regulated during normal erythropoiesis were opponently expressed in MDS containing putative new erythro-specific genes like two GTPase activator proteins, RAP1GA1 and ARHGAP8, which regulate small Rho GTPases. Fourteen of 22 continuously up-regulated genes during normal granulopoietic development displayed a significantly different expression in MDS containing the putative candidate desmocollin 2, a gene which is involved in intercellular cell-adhesion. Delta-like 1 (DLK1) is known to be overexpressed in stem cells from patients with myelodysplastic syndrome. The role of DLK1 in normal hematopoiesis is still not defined. We found DLK1 with increasing expression during normal megakaryopoiesis but reverse expression during megakaryopoiesis in MDS. Interestingly, in erythropoiesis from both, high- and low risk MDS we found overexpression of Bladder cancer overexpressed (BLOV1) and Apoptosis inhibitor 5 (API5, which acts as a cellular survival factor by inhibiting apoptosis after growth factor withdrawal). These genes are not expressed in normal erythropoiesis. Furthermore, we identified the gene for a novel v-maf-like protein F, MafF-like (v-maf: musculoaponeurotic fibrosarcoma oncogene homolog F) to be significantly downregulated exclusively in low-risk MDS. MafF belongs to a basic leucine-zipper(bZIP)-transcription factor family normally involved in multiple physiological processes including hematopoiesis and stress responses. Our data provide the first comprehensive transcriptional analysis of differentiating human CD34+ cells derived from normal individuals compared to MDS. It gives new insights to understand the alteration of differentiation and proliferation of MDS derived CD34+ cells. In particular, the study could identify the gene encoding for the MafF-like protein that acts as a transcriptional regulator of normal hematopoiesis to be significantly down-regulated in low-risk MDS.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.201.201
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    GATA and BCLxl Downregulation in Erythropoiesis during In Vitro Lineage Specific Differentiation of MDS Hematopoietic Progenitor Cells Is Not Induced by Activated Notch Pathway.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4118-4118
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4118-4118
    Abstract: Notch signals have recently been shown to inhibit erythroid and megakaryocytic differentiation of hematopoietic progenitor cells. In myelodysplastic syndrome (MDS) its role in dyserythropoiesis has not been fully elucidated. Therefore we asked whether dysregulation of Notch pathway elements might be associated with impaired GATA1 and BCLxl expression and ineffective erythropoiesis being a hallmark of MDS hematopoiesis. We have generated an in-vitro model of MDS lineage-specific hematopoietic differentiation by culturing CD34+ bone marrow cells from healthy donors (n=7) and MDS patients (low risk: RA/n=6, RARS/n=3; high risk: RAEB/n=4, RAEB-T/n=2) with EPO and TPO. Cell harvest was at days 0, 4, 7 and 11. Expression of GATA1, BCLxl, DLK1, Notch1, HES1 and HERP2 was measured by real time RT-PCR (qPCR). RNA expression of GATA1 and of BCLxl was steadily upregulated, particularly during late normal erythropoiesis. During normal megakaryopoiesis expression of both genes was up to 50 times lower as compared to normal erythropoiesis. In contrast, during MDS erythropoiesis a loss of typical late upregulation of GATA1 and BCLxl was observed. DLK1 expression during erythropoiesis showed increased expression particularly in high risk MDS vs. normal controls. Expression of HES1 was increasing during the course of normal erythropoietic and megakaryopoietic differentiation but not in lineage specific cells from MDS patients. In conclusion our data show that the central erythropoietic transcription factor GATA1 and the associated antiapoptotic molecule BCLxl are markedly downregulated during MDS erythropoiesis which may contribute to the ineffective erythropoiesis seen in this disease. Increased DLK1 expression in differentiated stem cells from high risk MDS patients was seen. However, an upregulation of the Notch pathway leading to increased expression of the GATA1 repressor HES1 could not be detected.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4118.4118
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    Significant Down-Regulation of BAALC during Lineage Specific Hematopoietic Differentiation.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 4189-4189
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 4189-4189
    Abstract: The human gene BAALC (Brain And Acute Leukemia, Cytoplasmic) implicated in normal hematopoiesis and leukemia is a marker of immature hematopoietic progenitor cells (PNAS2001;98:13901). To explore its role in hematopoiesis we investigated the regulation of BAALC during lineage specific differentiation. Semi-quantitative RT-PCR was performed on subsets of in vitro differentiated bone marrow CD34+ cells from healthy individuals using the cytokines G-CSF, M-CSF or EPO. Cultures were harvested on day 4, 8, 12, and 16. In addition, oligonucleotide microarray analyses (HG-U133A, Affymetrix) of in vitro stimulated CD34+ cells were independently carried out using EPO, TPO, G/GM-CSF to induce lineage-specific differentiation. For each of the lineages, cells were harvested at days 4, 7 and 11 for expression profiling. All experiments were done in triplicates for each time point and condition. RT-PCR revealed down-regulation of BAALC and CD34 as early as day 4 in cultures with G-CSF, M-CSF or EPO. In concordance, gene expression profiling showed significant down-regulation of BAALC and CD34 on day 4 of culture (BAALC: EPO p=0.04, G/GM-CSF p=0.17, TPO p=0.03; CD34: EPO p=0.01, G/GM-CSF p=0.003, TPO p=0.01). 275 genes showing a significant correlation (correlation coefficient r & gt;0.95) to BAALC expression levels (at the 4 time points and using 3 different cytokines) were identified. Of these CD34 ranked second (r=0.99), and genes related to leukemia and neuronal cells included: Hepatic leukemia factor (HLF; r=0.99) and Paired box gene 5 (PAX5; r=0.99). It has been speculated that BAALC might be involved in cell movement or cell-cell interaction; we therefore investigated the association to genes implicated in cytoskeletal function. Expression of Myosin 5C (MYO5C; r=0.99) and Synaptic nulcei expressed gene 2 (SYNE2; r=0.95) were highly correlated with BAALC expression across all conditions (EPO, TPO, G/GM-CSF). In conclusion, using two independent approaches we show the significant down-regulation of BAALC during hematopoietic differentiation. This underscores the potential role of BAALC in early hematopoiesis and the possible contribution of aberrant BAALC expression in leukemogenesis. We postulate that similar to CD34, PAX, and HLF implicated in hematopoiesis and leukemia, down-regulation of BAALC and structural genes including Myosin 5C are critical steps during hematopoietic differentiation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.4189.4189
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
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    Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy
    Springer Science and Business Media LLC ; 2009
    In:  Breast Cancer Research Vol. 11, No. 5 ( 2009-10)
    Details
    In: Breast Cancer Research, Springer Science and Business Media LLC, Vol. 11, No. 5 ( 2009-10)
    Type of Medium: Online Resource
    ISSN: 1465-542X
    URL: Article
    DOI: 10.1186/bcr2363
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
    detail.hit.zdb_id: 2041618-0
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  • 7
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    Identification of Putative New Tumor Suppressor Genes in Highly Purified CD34+ Bone Marrow Cells from Patients with Myelodysplastic Syndromes.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 204-204
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 204-204
    Abstract: Activation of transcription of DNA by demethylation and hyperacetylation is known to cause hematologic improvement in patients with myelodysplastic syndromes (MDS). In this study we discriminated genes not expressed in CD34+ cells from untreated patients with MDS but activated by in vitro demethylation (2-aza-5-deoxycytidine, Decitabine) and hyperacetylation (suberoylanilide hydroxamic acid, SAHA). Highly purified CD34+ cells from normal individuals (n=3) and patients with low (n=3) and high (n=3) risk MDS were cultured with SCF (50 ng/ml), IL-3 (10 ng/ml) and GM-CSF (10 ng/ml). The cells were treated with 5 μmol Decitabine on day 1 and supplemented with 2.5 μmol SAHA on day 4 of culture. On day 5, global gene expression in these cells was compared to untreated cells (HG-U133A, Affymetrix, Santa Clara, CA). We identified 50 genes which are not expressed in untreated MDS CD34+ cells but 3-fold induced in all MDS samples by Decitabine and SAHA. Thirty-one of these genes were found to be expressed in normal CD34+ cells underlining the importance of such genes for normal hematopoiesis. This set of genes includes two genes for growth arrest and DNA damage control, the inducible protein beta (GADD45B), a regulator of growth and apoptosis and neural cell adhesion molecule 1 (NCAM1) that plays an important role in cell migration. Furthermore, hematological and neurological expressed 1 (HN1) which was not expressed in MDS CD34+ cells is known to have an anti-proliferative effect on tumor cell lines. N-myc downstream regulated 3 (NDRG3) is up-regulated during normal cell differentiation and suppressed in several tumor cells. In normal CD34+ cells, after in vitro treatment with Decitabine and SAHA we have discriminated 52 genes to be 3-fold up-regulated compared to untreated cells. Thirty-eight of these genes (73 %) were not inducible by demethylation and hyperacetylation in MDS CD34+ cells. These genes include chemokine receptor 3 (CCR3), a receptor for a C-C type chemokine involved in signal transduction, integrin beta-7 (ITGB7) that plays a role in adhesive interactions of leukocytes, preferentially expressed antigen in melanoma (PRAME) which is frequently expressed in human solid cancers and acute leukemia and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) that recruits apoptotic suppressors and mediates most of the metabolic effects of TNF-alpha. The silencing of these genes is independent of methylation and acetylation state and might be due to other mechanisms. This study shows that in CD34+ cells from MDS patients several genes are suppressed by methylation and hypoacetylation but can be activated by treatment with Decitabine and SAHA. Some of these genes are present in normal untreated CD34+ cells which leads to the assumption that they might function as tumor suppressor genes. Low or absent expression of these genes may contribute to the clonal expansion of MDS CD34+ which can be overcome by treatment with Decitabine or SAHA. Furthermore, the knowledge about these target genes may enable a more specific evaluation of the mechanisms of action of demethylating/hyperacetylating agents.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.204.204
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Survivin Isoforms and HSP90 Are Downregulated in Erythropoiesis during Lineage Specific Differentiation of MDS Hematopoietic Progenitor Cells.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 2541-2541
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2541-2541
    Abstract: Survivin has recently been shown to critically regulate erythroid versus megakaryocytic differentiation in mouse hematopoietic stem cells. Its role in human hematopoiesis has not been fully elucidated yet. To answer the question whether dysregulation of expression of survivin and its protein stabilisator HSP90 contributes to the ineffective erythropoiesis in myelodysplastic syndrome (MDS), we have generated an in vitro model of MDS lineage-specific hematopoietic differentiation by culturing CD34+ cells from healthy donors (n=7) and MDS patients (low risk: RA/n=6, RARS/n=3; high risk: RAEB/n=4, RAEB-T/n=2) with EPO, TPO and GCSF. Cell harvest was at days 0, 4, 7 and 11. Expression analysis of survivin splicing variants (wt, 2a, d3ex) and of HSP90 was done by real time RT-PCR (qPCR) for each lineage at each time point. Furthermore, epigenetic analysis of key regulatory genes by methylation specific PCR and qPCR to detect DNMT1 (maintenance methylation) and DNMT3a and 3b (de novo methylation) expression was performed for each of the experimental conditions. RNA expression of all survivin isoforms and of HSP90 was continously upregulated during normal erythropoiesis. During late megakaryopoiesis of normal hematopoietic stem cells a significant downregulation was seen with elevated expression values for survivin wt and survivin 2b during early thrombopoiesis. In contrast, during MDS erythropoiesis a significant downregulation of expression of all survivin isoforms and HSP90 during late erythropoiesis was observed. Lower expression for survivin wt, survivin 2b and HSP90 was seen during early MDS megakaryopoiesis. Promotor methylation analyisis revealed MDS specific aberrant methylation for survivin, particularly during MDS high risk erythropoiesis (p=0.02). However, expression of DNMT1 was only elevated during erythropoiesis and in low risk MDS. A significant inverse correlation between RNA expression of DNMT enzymes and survivin splicing variants could not be detected. In conclusion our data support the essential role for survivin in regulation of erythropoietic versus megakaryopoietic differentiation of hematopoietic precursor cells. The dysregulation of survivin expression during MDS erythropoiesis may therefore account for the ineffective erythropoiesis known in MDS. Furthermore, downregulation of survivin (protein) stabilisator HSP90 might additionally contribute to this effect. Although an inverse correlation with overexpression of DNMTs and downregulation of survivin splicing variants was not seen, the aberrant survivin promoter methylation during MDS erythropoiesis indicates that epigenetic dysregulation results in low survivin expression.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2541.2541
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Inhibitory effect of imatinib on normal progenitor cells in vitro
    American Society of Hematology ; 2004
    In:  Blood Vol. 103, No. 2 ( 2004-01-15), p. 523-529
    Details
    In: Blood, American Society of Hematology, Vol. 103, No. 2 ( 2004-01-15), p. 523-529
    Abstract: Imatinib is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome–positive leukemias and other malignancies. Side effects are mostly moderate; however, a dose-dependent hematologic toxicity affecting all hematopoietic lineages is observed clinically. The aim of this study was to investigate the effect of imatinib on normal hematopoietic stem and progenitor cells in vitro. A dose-dependent decrease in proliferation potential was found when CD34+ cells were expanded in serum-free medium supplemented with 6 growth factors and imatinib. Functionally, a decrease in colony-forming capacity was observed under increasing doses of imatinib. However, no such effect on more primitive cobblestone area–forming cells was detectable. Both withdrawal of stem cell factor from our expansion cultures or functional inhibition of c-kit led to a similar degree of inhibition of expansion, whereas the effect of imatinib was substantially greater at all dose levels tested. These data suggest a significant inhibitory effect of imatinib on normal CD34+ progenitor (but not stem) cells that is largely independent of c-kit signaling.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2003-05-1535
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Tumor-Associated Lymphocytes As an Independent Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer
    American Society of Clinical Oncology (ASCO) ; 2010
    In:  Journal of Clinical Oncology Vol. 28, No. 1 ( 2010-01-01), p. 105-113
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 1 ( 2010-01-01), p. 105-113
    Abstract: Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. Methods We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell–related markers CD3D and CXCL9 with pCR. Conclusion The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2009.23.7370
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
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