Hans Kreipe

Hannover Medical School, Hanover, Lower Saxony, Germany

Are you Hans Kreipe?

Claim your profile

Publications (339)1387.88 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic histiocytic intervillositis of the placenta (CHI) shows monocytic/histiocytic infiltration of the intervillous space. Placental malaria has a CHI-like histopathology and induces an aberrant expression of Toll-like receptors (TLR) 3, 7-9. We hypothesized that, similar to placental malaria, CHI could be associated with increased TLR expression. TLR1-10 and other inflammation-associated factors were analyzed by real-time PCR and immunohistochemistry. A total of 31 formalin-fixed and paraffin-embedded placenta samples were evaluated: CHI (n = 9), and for control purposes, villitis of unknown etiology (VUE, n = 8) and placentas without inflammation (n = 14). CHI shows increased expression of monocytic TLR1, a receptor which is involved in bacterial lipopolysaccharide (LPS)-induced inflammation. This could indicate a TLR1-mediated immune mechanism in the placenta (e.g. triggered by transient, clinically inapparent maternal bacteraemia) which leads to massive monocytic/histiocytic accumulation in the intervillous space. The increased expression of TLR1 with no increased expression of TLR3 and TLR7-9 is different from that in malaria.
    Fetal and pediatric pathology 10/2015; DOI:10.3109/15513815.2015.1095259 · 0.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic lung allograft dysfunction (CLAD) is the main reason for poor long-term outcome of lung transplantation, with bronchiolitis obliterans (BO) representing the predominant pathological feature. BO is defined as a progressive fibrous obliteration of the small airways, thought to be triggered by a combination of nonimmune bronchial injury and alloimmune and autoimmune mechanisms. Because biopsy samples are too insensitive to reliably detect BO and a decline in lung function test results, which is clinically used to define CLAD, does not detect early stages, there is need for alternative biomarkers for early diagnosis. Herein, we analyzed the cellular composition and differential expression of 45 tissue remodeling-associated genes in transbronchial lung biopsy specimens from two cohorts with 18 patients each: patients who did not develop CLAD within 3 years after transplantation (48 biopsy specimens) and patients rapidly developing CLAD within the first 3 postoperative years (57 biopsy specimens). Integrating the mRNA expression levels of the five most significantly dysregulated genes from the transforming growth factor-β axis (BMP4, IL6, MMP1, SMAD1, and THBS1) into a score, patient groups could be confidently separated and the outcome predicted (P < 0.001). We conclude that overexpression of fibrosis-associated genes may be valuable as a tissue-based molecular biomarker to more accurately diagnose or predict the development of CLAD.
    American Journal Of Pathology 10/2015; DOI:10.1016/j.ajpath.2015.08.016 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Aberrant DNA methylation at imprinted loci is an important molecular mechanism contributing to several developmental and pathological disorders including cancer. However, knowledge about imprinting defects due to DNA methylation changes is relatively limited in hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide. Therefore, comprehensive quantitative DNA methylation analysis at imprinted loci showing ~50 % methylation in healthy liver tissues was performed in primary HCC specimens and the peritumoural liver tissues. Results: We found frequent and extensive DNA methylation aberrations at many imprinted loci in HCC. Unsupervised cluster analysis of DNA methylation patterns at imprinted loci revealed subgroups of HCCs with moderate and severe loss of methylation. Hypomethylation at imprinted loci correlated significantly with poor overall survival (log-rank test, p = 0.02). Demethylation at imprinted loci was accompanied by loss of methylation at LINE-1, a commonly used marker for global DNA methylation levels (p < 0.001). In addition, we found that loss of methylation at imprinted loci correlated with the presence of a CTNNB1 mutation (Fisher's exact test p = 0.03). Re-analysis of publically available genome-wide methylation data sets confirmed our findings. The analysis of benign liver tumours (hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH)), the corresponding adjacent liver tissues, and healthy liver tissues showed that aberrant DNA methylation at imprinted loci is specific for HCC. Conclusions: Our analyses demonstrate frequent and widespread DNA methylation aberrations at imprinted loci in human HCC and identified a hypomethylated subgroup of patients with shorter overall survival.
    Clinical Epigenetics 10/2015; 7(1):110. DOI:10.1186/s13148-015-0145-6 · 4.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431). Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients. Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients.
    Leukemia Research 09/2015; DOI:10.1016/j.leukres.2015.09.003 · 2.35 Impact Factor
  • Angelika Stucki-Koch · Gesa Hauck · Hans Kreipe · Kais Hussein ·

    09/2015; DOI:10.1007/s12308-015-0258-z
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: In the era of potentially disease modifying agents like JAK inhibitors, accurate grading and differentiation of bone marrow (BM) fibrosis has become more relevant to assess staging of disease and therapeutic effects. However, different fibrosis grading models were used in the past without uniformity including the proposal by the World Health Organization. Current scoring systems are based only on reticulin fibrosis. Therefore additional assessment of collagen and the grade of osteosclerosis appear to be essential to discriminate all components of the complex BM fibrous matrix. Methods and results: We evaluated problems and pitfalls regarding staining techniques and the interpretation of reticulin fibrosis on a total of 352 samples. Furthermore, we propose a minor modification of the current grading, and separate scoring for collagen deposition and osteosclerosis. Reproducibility of gradings was tested among 11 haematopathologists in a blinded assessment. Overall the inter-rater reliability of all three grading systems ranged between 0.898 and 0.926. Conclusions: standardized assessment of BM fibrosis with differentiation between reticulin, collagen, and osteosclerosis is recommended to evaluate the various components of the fibrous matrix which may be delinked after therapy. In this regard quality of staining and application of laboratory standards enable a highly reproducible scoring. This article is protected by copyright. All rights reserved.
    Histopathology 09/2015; DOI:10.1111/his.12871 · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Most breast cancers depend on estrogenic growth stimulation. Functional genetic screenings in in vitro cell models have identified genes, which override growth suppression induced by anti-estrogenic drugs like tamoxifen. Using that approach, we have previously identified Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) as a mediator of cell proliferation and tamoxifen-resistance. Here, we show high level of expression and function of BCAR4 in human breast cancer. Methods: BCAR4 mRNA expression was evaluated by (q)RT-PCR in a panel of human normal tissues, primary breast cancers and cell lines. A new antibody raised against C78-I97 of the putative BCAR4 protein and used for western blot and immunoprecipitation assays. Furthermore, siRNA-mediated gene silencing was implemented to study the function of BCAR4 and its downstream targets ERBB2/3. Results: Except for placenta, all human normal tissues tested were BCAR4-negative. In primary breast cancers, BCAR4 expression was comparatively rare (10%), but associated with enhanced proliferation. Relative high BCAR4 mRNA expression was identified in IPH-926, a cell line derived from an endocrine-resistant lobular breast cancer. Moderate BCAR4 expression was evident in MDA-MB-134 and MDA-MB-453 breast cancer cells. BCAR4 protein was detected in breast cancer cells with ectopic (ZR-75-1-BCAR4) and endogenous (IPH-926, MDA-MB-453) BCAR4 mRNA expression. Knockdown of BCAR4 inhibited cell proliferation. A similar effect was observed upon knockdown of ERBB2/3 and exposure to lapatinib, implying that BCAR4 acts in an ERBB2/3-dependent manner. Conclusion: BCAR4 encodes a functional protein, which drives proliferation of endocrine-resistant breast cancer cells. Lapatinib, a clinically approved EGFR/ERBB2 inhibitor, counteracts BCAR4-driven tumor cell growth, a clinical relevant observation.
    PLoS ONE 08/2015; 10(8):e0136845. DOI:10.1371/journal.pone.0136845 · 3.23 Impact Factor
  • Source
    Stephan Bartels · Elisa Schipper · Hans Heinrich Kreipe · Ulrich Lehmann ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Comprehensive mutation profiling becomes more and more important in hematopathology complementing morphological and immunohistochemical evaluation of fixed, decalcified and embedded bone marrow biopsies for diagnostic, prognostic and also predictive purposes. However, the number and the size of relevant genes leave conventional Sanger sequencing impracticable in terms of costs, required input DNA, and turnaround time. Since most published protocols and commercially available reagents for targeted resequencing of gene panels are established and validated for the analysis of fresh bone marrow aspirate or peripheral blood it remains to be proven whether the available technology can be transferred to the analysis of archival trephines. Therefore, the performance of the recently available Ion AmpliSeq AML Research panel (LifeTechnologies) was evaluated for the analysis of fragmented DNA extracted from archival bone marrow trephines. Taking fresh aspirate as gold standard all clinically relevant mutations (n = 17) as well as 25 well-annotated SNPs could be identified reliably with high quality in the corresponding archival trephines of the training set (n = 10). Pre-treatment of the extracted DNA with Uracil-DNA-Glycosylase reduced the number of low level artificial sequence variants by more than 60%, vastly reducing time required for proper evaluation of the sequencing results. Subsequently, randomly picked FFPE samples (n = 41) were analyzed to evaluate sequencing performance under routine conditions. Thereby all known mutations (n = 43) could be verified and 36 additional mutations in genes not yet covered by the routine work-up (e.g., TET2, ASXL1, DNMT3A), demonstrating the feasibility of this approach and the gain of diagnostically relevant information. The dramatically reduced amount of input DNA, the increase in sensitivity as well as calculated cost-effectiveness, low hands on , and turn-around-time, necessary for the analysis of 237 amplicons strongly argue for replacing Sanger sequencing by this semiconductor-based targeted resequencing approach.
    PLoS ONE 07/2015; 10(7):e0133930. DOI:10.1371/journal.pone.0133930 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The nasopharyngeal/oropharyngeal lymphatic tissues represent the anatomical site of Epstein-Barr virus (EBV) entry. Post-transplant lymphoproliferative disorders (PTLD) are often associated with EBV but little is known about the characteristics of nasopharyngeal/oropharyngeal mass-forming PTLD. Retrospective evaluation of our own PTLD database (n=79) and the PubMed(®) database (n=61). Sinonasal/oro-/nasopharyngeal lymphatic masses were early lesions (n=54/140, 38.5%), polymorphic PTLD (n=32/140, 23%), monomorphic B-PTLD (n=47/140, 33.5%) and T-PTLD (n=7/140, 5%). One fourth of lesions manifested as masses in the Waldeyer's ring and in two thirds of cases, swelling of tonsils was related to manifestation of benign early lesions. Tonsil infiltration by polymorphic PTLD and monomorphic PTLD were present in one third of cases. Extra-tonsillar masses were mainly monomorphic PTLD. Metaanalysis of our data in combination with previously published data revealed that lung transplantion and young patients are at a higher risk for earlier manifestation of monomorphic PTLD. Therapy is similar to PTLD therapy strategies in general: reduced immunosuppression and chemotherapy for polymorphic and monomorphic PTLD, diagnostic and therapeutic surgical gross tumour resection of tonsillar/adenoid lesions. In summary, it is relevant for the clinical differential diagnosis that oro-/nasopharyngeal aggressive PTLD manifested in ~30% as tonsillar masses and >90% at extra-tonsillar sites. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant International 07/2015; 28(11). DOI:10.1111/tri.12632 · 2.60 Impact Factor

  • Senologie - Zeitschrift für Mammadiagnostik und -therapie 06/2015; 12(02):74-84. DOI:10.1055/s-0035-1553204
  • [Show abstract] [Hide abstract]
    ABSTRACT: Assessing alterations of the parenchymal architecture is essential in understanding fibrosing interstitial lung diseases. Here, we present a novel method to visualise fibrotic remodelling in human lungs and correlate morphological three-dimensional (3D) data with gene and protein expression in the very same sample. The key to our approach is a novel embedding resin that clears samples to full optical transparency and simultaneously allows 3D laser tomography and preparation of sections for histology, immunohistochemistry and RNA isolation. Correlating 3D laser tomography with molecular diagnostic techniques enables new insights into lung diseases. This approach has great potential to become an essential tool in pulmonary research. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 06/2015; DOI:10.1136/thoraxjnl-2015-207131 · 8.29 Impact Factor
  • Source

    Geburtshilfe und Frauenheilkunde 06/2015; DOI:10.1055/s-0035-1546120 · 0.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The key topics of this year's 14th St. Gallen Consensus Conference on the diagnosis and therapy of primary breast cancer were again questions about breast surgery and axillary surgery, radio-oncology and systemic therapy options in consideration of tumor biology, and the clinical application of multigene assays. This year, the consensus conference took place in Vienna. From a German perspective, it makes sense to substantiate the results of the vote of the international panel representing 19 countries in light of the updated national therapy recommendations of the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie). Therefore, 14 German breast cancer experts, 3 of whom are members of the International St. Gallen Panel, have commented on the voting results of the St. Gallen Consensus Conference 2015 in relation to clinical routine in Germany.
    Breast Care 06/2015; 10(3):211-219. DOI:10.1159/000433590 · 0.63 Impact Factor

  • Journal of Clinical Oncology 06/2015; 33(Suppl.):abstrakt 506. · 18.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic decision-making in breast cancer depends on histopathologic biomarkers and is influenced by the Ki67 proliferation index. Computer-assisted image analysis (CAIA) promises to improve Ki67 quantification. Several commercial applications have been developed for semiautomated CAIA-based Ki67 quantification, many of which rely on measurements in user-defined regions of interest (ROIs). Because of intratumoral proliferative heterogeneity, definition of the ROI is an important step in the analytical procedure. This study explores the ROI size impacts on Ki67 quantification. Whole-slide sections of 100 breast cancers were immunostained with the anti-Ki67 antibody 30-9 and were analyzed on the iScan Coreo digital pathology platform using a Food and Drug Administration-cleared Ki67 quantification software version v5.3 (Virtuoso; Ventana, Tucson, TX). For each case, the Ki67 labeling index (LI) was determined in multiple ROIs of gradually increasing size centered around a high-proliferation area. The spatial Ki67 decline was modeled with nonlinear regression. Depending on the ROI size, the median Ki67 LI varied between 55% and 15%. The proportion of tumors classified as Ki67 low according to the St Gallen 2013/2015 cutoff increased from 2% to 56%, as the ROI size increased from 50 to 10 000 cells captured. The interrater reliability of conventional Ki67 assessment versus CAIA-based Ki67 quantification was also dependent on the ROI size and varied between slight and almost perfect agreement (Cohen κ = 0.06-0.85). In conclusion, the ROI size is a critically important parameter for semiautomated Ki67 quantification by CAIA. Ki67 LIs determined on platforms like iScan Coreo/Virtuoso require an ROI size adjustment, for which we offer a downloadable data transformation tool. Copyright © 2015. Published by Elsevier Inc.
    Human pathology 05/2015; 46(9). DOI:10.1016/j.humpath.2015.05.016 · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spindle cell/mesenchymal tumors of the kidney are rare. The diagnosis is supported mainly by the application of ancillary techniques such as immunohistochemistry (IH) and in-situ hybridization (FISH). An accurate diagnosis is essential because early management by complete resection and adjuvant chemotherapy improves the prognosis dramatically. Synovial sarcoma and primitive neuroectodermal tumor/Ewing sarcoma are infrequent malignancies which usually present in soft tissues but rarely in the kidney. The challenge for the pathologists is to histologically differentiate between different types of sarcomas such as PNET/Ewing's sarcoma, sarcomatous dedifferentiated renal cell carcinoma, metastasis, non-Hodgkin's lymphoma, nephroblastoma and angiomyolipoma. We report from our experience six exemplary rare cases that presented in the kidney as spindle/round cell tumors. We have arrived at the accurate diagnosis after performing a large panel of IH and FISH. In summary we advise an immunohistochemical panel for round/spindle cell tumors of the kidney and for unclear cases we advise to add (FISH) to get the correct diagnosis, as they are completely different regarding surgical approach and post-operative adjuvant therapy. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.
    Journal of the Egyptian National Cancer Institute 05/2015; 9(3). DOI:10.1016/j.jnci.2015.04.005
  • [Show abstract] [Hide abstract]
    ABSTRACT: Here we report on a child with Li-Fraumeni syndrome with a de novo TP53 mutation c.818G>A, who developed three malignancies at the age of 4 months, 4 and 5 years, respectively. We show that (i) in the choroid plexus carcinoma, the germline mutation was detected in a homozygous state due to copy-neutral LOH/uniparental disomy, (ii) in the secondary AML, a complex karyotype led to loss of the wild-type TP53 allele, (iii) in the Wilms tumor, the somatic mutation c.814G>A led to compound heterozygosity. The findings show that the complete inactivation of TP53 by different mechanisms is an important step towards tumorigenesis. Pediatr Blood Cancer 2015; 9999:1-4. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2015; 62(8). DOI:10.1002/pbc.25486 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Taxane-anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 ≥ 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38-0.986), age <50 years old (HR = 1.682; 95 %CI 1.025-2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809-11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209-4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203-0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis.
    Breast Cancer Research and Treatment 02/2015; 150(2). DOI:10.1007/s10549-015-3310-x · 3.94 Impact Factor
  • M E Dämmrich · H H Kreipe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: In breast surgery, replacement of intraoperative frozen section by core needle and vacuum biopsies hampers collections of unfixed breast specimens. We practice immediate intraoperative macroscopic analysis of resection margins and vacuum-cooling of breast specimens to enable native tissue asservation for assessment of biological markers and tissue banking of tumor tissue. In addition, slicing of native tissue before formalin fixation guarantees a standardized and uniform fixation. Starting in 2013, more than 350 breast specimens were processed as native specimens in the Institute of Pathology of Hannover Medical School. Breast specimens with an invasive carcinoma and request of an intraoperative resection margin assessment were processed with an immediate intraoperative pathological analysis. All other breast specimens without assessment of an intraoperative resection margin were vacuum-fixed processed. In all cases, native tissue for biomarker analyses and tumor banking could be preserved.
    Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2015; 199:45-53. DOI:10.1007/978-3-319-13957-9_5

  • Cancer Research 12/2014; 74(25):P4-15-01. DOI:10.1158/1538-7445.SABCS14-P4-15-01 · 9.33 Impact Factor

Publication Stats

7k Citations
1,387.88 Total Impact Points


  • 2000-2015
    • Hannover Medical School
      • Institute for Pathology
      Hanover, Lower Saxony, Germany
  • 2007
    • Hochschule Hannover
      Hanover, Lower Saxony, Germany
    • Institut für Pathologie und Molekularpathologie
      Gelsenkirchen, North Rhine-Westphalia, Germany
  • 2001
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1996-1998
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany