Hans Kreipe

Hannover Medical School, Hanover, Lower Saxony, Germany

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Publications (319)1305.69 Total impact

  • [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 · 8.56 Impact Factor
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    ABSTRACT: Therapeutic decision-making in breast cancer depends on histopathological 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 semi-automated CAIA-based Ki67 quantification, many of which rely on measurements in user-defined regions of interest (ROIs). Due to intratumoral proliferative heterogeneity, definition of the ROI is an important step in the analytical procedure. This study explores inasmuch the ROI size impacts on Ki67 quantification.
    Human pathology 05/2015; DOI:10.1016/j.humpath.2015.05.016 · 2.81 Impact Factor
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    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. DOI:10.1016/j.jnci.2015.04.005
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    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; DOI:10.1002/pbc.25486 · 2.56 Impact Factor
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    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 · 4.20 Impact Factor
  • Cancer Research 12/2014; 74(25):P4-15-01. DOI:10.1158/1538-7445.SABCS14-P4-15-01 · 9.28 Impact Factor
  • Cancer Research 12/2014; 74(Suppl.):P4-11-01. DOI:10.1158/1538-7445.SABCS14-P4-11-01 · 9.28 Impact Factor
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    ABSTRACT: Comprehensive spatial assessment of hormone receptor immunohistochemistry staining in digital whole slide images of breast cancer requires accurate detection of positive nuclei within biologically relevant regions of interest. Herein, we propose a combination of automated region labeling at low resolution and subsequent detailed tissue evaluation of subcellular structures in lobular structures adjacent to breast cancer, as a proof of concept for the approach to analyze estrogen and progesterone receptor expression in the spatial context of surrounding tissue. Routinely processed paraffin sections of hormone receptor-negative ductal invasive breast cancer were stained for estrogen and progesterone receptor by immunohistochemistry. Digital whole slides were analyzed using commercially available image analysis software for advanced object-based analysis, applying textural, relational, and geometrical features. Mammary gland lobules were targeted as regions of interest for analysis at subcellular level in relation to their distance from coherent tumor as neighboring relevant tissue compartment. Lobule detection quality was evaluated visually by a pathologist. After rule set optimization in an estrogen receptor-stained training set, independent test sets (progesterone and estrogen receptor) showed acceptable detection quality in 33% of cases. Presence of disrupted lobular structures, either by brisk inflammatory infiltrate, or diffuse tumor infiltration, was common in cases with lower detection accuracy. Hormone receptor detection tended towards higher percentage of positively stained nuclei in lobules distant from the tumor border as compared to areas adjacent to the tumor. After adaptations of image analysis, corresponding evaluations were also feasible in hormone receptor positive breast cancer, with some limitations of automated separation of mammary epithelial cells from hormone receptor-positive tumor cells. As a proof of concept for object-oriented detection of steroid hormone receptors in their spatial context, we show that lobular structures can be classified based on texture-based image features, unless brisk inflammatory infiltration disrupts the normal morphological structure of the tubular gland epithelium. We consider this approach as prototypic for detection and spatial analysis of nuclear markers in defined regions of interest. We conclude that advanced image analysis at this level of complexity requires adaptation to the individual tumor phenotypes and morphological characteristics of the tumor environment.
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    ABSTRACT: Background: Aberrations in DNA methylation patterns are well-described in human malignancies. However, the existence of the 'CpG island methylator phenotype' (CIMP) in human breast cancer is still controversial. Materials & methods: Illumina's HumanMethylation 450K BeadChip was used to analyze genome-wide DNA methylation patterns. Chromosomal abnormalities were determined by array-based CGH. Results: Invasive lobular breast carcinomas exhibit the highest number of differentially methylated CpG sites and a strong inverse correlation of aberrant DNA hypermethylation and copy number alterations. Nine differentially methylated regions within seven genes discriminating the investigated subgroups were identified and validated in an independent validation cohort and correlated to a better relapse-free survival. Conclusion: These results depict a clear difference between genetically and epigenetically unstable breast carcinomas indicating different ways of tumor progression and/or initiation, which strongly supports the association of CIMP with the lobular subtype and provide new options for detection and therapy.
    Epigenomics 10/2014; 7(2):1-13. DOI:10.2217/epi.14.74 · 5.22 Impact Factor
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    ABSTRACT: Fine needle aspiration (FNA) is a sensitive and specific method (95%), often helpful in characterizing suspected liver lesions. It is appropriate to distinguish between primary and secondary liver neoplasia. Moreover, in most cases, the use of cell block preparations of small specimens allows immunocytochemical evaluation to determine the nature of the primary tumour. In a retrospective study at Hannover Medical School (MHH) from 1998 to 2012 (14 years), 4,136 sonographically guided FNAs were performed. The patients provided consent and the study protocol was approved by the local ethics committee. There were 39.6% malignant and 57.5% benign lesions in the liver, while 2.8% of the cases were undetermined. FNA was non-representative in 1.1% of the cases. The diagnostic utility of highly differentiated hepatocellular carcinoma (HCC; G1) remains difficult; cell bridges with cell atypia are pathognomonic for diagnosis. Ancillary techniques and immunocytochemical investigations will increase the sensitivity and specificity, particularly by using the cell block technique.
    Oncology Reports 10/2014; 33(1). DOI:10.3892/or.2014.3554 · 2.19 Impact Factor
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    ABSTRACT: Metastasis to the periocular soft tissue of the orbit is a rare manifestation of metastatic cancer. Infiltrating lobular breast cancer (ILBC) is a special breast cancer subtype, which accounts for 10–15% of all mammary carcinomas and for ~1% of all malignancies. Here, we report on a high frequency of lobular breast cancer in patients with orbital metastases identified in an original series of metastatic tumor specimens and by a systematic literature review. A series of 14 orbital metastases was compiled from formalin-fixed paraffin-embedded archival tissues. All cases were subjected to histological re-review and detailed immunophenotypical characterization. In addition, we performed a meta-analysis of 68 previously published case reports describing orbital metastases, with special reference to breast cancer subtypes. Based on clinical history, histomorphology, immunophenotype, and/or comparison with matched primary tumors, orbital metastases were derived from breast cancer in 8/14 cases, seven of which were classified as metastatic lobular breast cancer. Other entities included non-small cell lung cancer (4/14), infiltrating ductal breast cancer (1/14), prostate cancer (1/14) and adenocarcinoma of the esophagus (1/14). In line with this original series of orbital metastases, lobular breast cancer was the most common malignancy in 72 patients with orbital metastases described in 68 independent case reports. In conclusion, lobular breast cancer represents the cancer subtype with the highest prevalence among orbital metastases. The high frequency of ILBC in orbital metastases illustrates the special metastatic behavior of this tumor entity and may have implications for the understanding of the organotropism of metastatic lobular breast cancer.
    Cancer Medicine 10/2014; 4(1). DOI:10.1002/cam4.331
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    ABSTRACT: Humans and dogs are affected by squamous cell carcinomas of the oral cavity (OSCC) in a considerably high frequency. The high mobility group A2 (HMGA2) protein was found to be highly expressed in human OSCC and its expression was suggested to act as a useful predictive and prognostic tool in clinical management of oral carcinomas. Herein the expression of HMGA2 and its sister gene HMGA1 were analysed within human and canine OSCC samples. Additionally, the HMGA negatively regulating miRNAs of the let-7 family as well as the let-7 regulating gene Lin28 were also comparatively analysed. Deregulations of either one of these members could affect the progression of human and canine OSCC.
    BMC Cancer 09/2014; 14(1):694. DOI:10.1186/1471-2407-14-694 · 3.32 Impact Factor
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    Leukemia and Lymphoma 09/2014; 56(3):1-10. DOI:10.3109/10428194.2014.941837 · 2.61 Impact Factor
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    ABSTRACT: Rare Epstein–Barr virus (EBV)+ smooth muscle tumours (SMT) manifest typically under immunosuppression. Three major subtypes are known: human immunodeficiency virus-associated (HIV-SMT), after transplantation (PTSMT) or associated with congenital immunodeficiency syndromes (CI-SMT). So far, there are no analyses which compare the clinico-pathological characteristics of all three subtypes. Case reports and case series on these three tumour types were collected (1990–2012). Meta-data analysis was performed for identification of similarities and differences. A total of 73 HIV-SMT, 66 PTSMT and 9 CI-SMT were evaluated. There was a slight female predominance (55–67%). Children were affected nearly equally in HIV-SMT (33%) and PTSMT (35%), while all CI-SMT occurred in children. HIV-SMT manifested preferentially in the central nervous system, gut/liver, skin, lungs/larynx/pharynx and adrenal glands. PTSMT were predominantly found in the liver, lungs/larynx/pharynx, gut/spleen and brain. CI-SMT were often found in lungs/larynx, brain, liver, adrenal glands and spleen. Antecedent EBV+ lymphoproliferations manifested more often in PTSMT. In all three tumour subtypes, survival analyses did not show any significant differences regarding surgical therapeutic approaches, the occurrence of multiple tumours, tumour size or sarcoma-like histological features. HIV-SMT had the poorest overall survival, which might be attributed to HIV-associated infectious complications.
    European Journal of Cancer 09/2014; 50(14). DOI:10.1016/j.ejca.2014.06.006 · 4.82 Impact Factor
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    ABSTRACT: Objectives Caspase 14 is reduced in adenocarcinomas of the stomach and colon. In contrast, breast and lung adenocarcinomas frequently show an overexpression of caspase 14. Salivary gland adenocarcinomas have not been evaluated for potential aberrant caspase 14 expression.Materials and Methods Samples from salivary gland carcinomas (n = 43) were analysed by immunohistochemistry (caspase 14, filaggrin, GATA3 and Ki67) and fluorescence in situ hybridization.ResultsCaspase 14 is not expressed in normal salivary glands, while in a subfraction of carcinomas (32%) an aberrant expression was found. Filaggrin could not be detected. Caspase 14 staining was not associated with tumour dedifferentiation, GATA3 expression or amplification of gene locus 19p13.Conclusion In summary, aberrant expression of caspase 14 can be found in a subfraction of salivary gland carcinomas but could not be used as a biomarker for a specific carcinoma subtype of the salivary gland.
    Journal of Oral Pathology and Medicine 09/2014; 44(6). DOI:10.1111/jop.12253 · 1.87 Impact Factor
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    ABSTRACT: Routinely processed skin biopsies are still the mainstay for the diagnosis of melanocytic skin neoplasms (MSNs) and are considered the "gold standard" for individual patient management and clinical trials. The diagnostic challenge of melanocytic lesions of the skin prompts histopathologists to consider new diagnostic tools; among these, immunohistochemistry. We aimed to find putative new immunohistochemical markers, which can supplement the histological criteria used to detect dysplasia. In this immunohistochemical study, we chose a panel of promising biomarkers which could potentially differentiate between different MSN entities. These included α-methylacyl-coenzyme A racemase (AMACR; p504s), which is involved in the degradation of branched chained fatty acid derivates. We analysed a cohort of benign nevi and malignant melanomas. The design of the study included 78 melanocytic skin neoplasms (26 malignant melanomas and 52 benign nevi) in a tissue microarray. Immunohistochemistry of cyclin-dependent kinase inhibitor 2A (p16Ink4a), methylacyl-coenzyme A racemase (AMACR), cyclin D1, and E-cadherin was performed and assessed. We have observed that the p16Ink4a, AMACR, cyclin D1, and E-cadherin showed no exclusive staining for nevi or melanomas. However, a significant overexpression of AMACR was found in malignant melanomas compared to benign nevi. AMACR overexpression was also associated with an increased p16Ink4a staining. Our results suggest AMACR as an immunohistochemical marker for distinguishing malignant melanomas and dysplastic nevi from conventional melanocytic nevi.
    Tumor Biology 08/2014; DOI:10.1007/s13277-014-2500-1 · 2.84 Impact Factor
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    ABSTRACT: The tumour suppressor gene RB1 is frequently silenced in many different types of human cancer including hepatocellular carcinoma (HCC). However, mutations of the RB1 gene are relatively rare in HCC. A systematic screen for the identification of imprinted genes deregulated in human HCC revealed that RB1 shows imprint abnormalities in a high proportion of primary patient samples. Altogether 40% of the HCC specimens (16/40) showed hyper -or hypomethylation at the CpG island in intron 2 of the RB1 gene. Re-analysis of publicly available genome-wide DNA methylation data confirmed these findings in two independent HCC cohorts. Loss of correct DNA methylation patterns at the RB1 locus leads to the aberrant expression of an alternative RB1-E2B transcript as measured by quantitative real-time PCR.Demethylation at the intron 2 CpG island by DNMT1 knockdown or aza-deoxycytidine (DAC) treatment stimulated expression of RB1-E2B transcript accompanied by diminished RB1 main transcript expression. No aberrant DNA methylation was found at the RB1 locus in hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5) and their corresponding adjacent liver tissue specimens. Deregulated RB1 expression due to hyper- or hypomethylation in intron 2 of the RB1 gene is found in tumours without loss of heterozygosity and is associated with a decrease in overall survival (p = 0.032) if caused by hypermethylation of CpG85. This unequivocally demonstrates that loss of imprinting represents an important additional mechanism for RB1 pathway inactivation in human HCC complementing well-described molecular defects.
    The Journal of Pathology 08/2014; 233(4). DOI:10.1002/path.4376 · 7.33 Impact Factor
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    ABSTRACT: It is known that human papillomavirus (HPV) infection can cause squamous cell neoplasms at several sites, such as cervix uteri carcinoma and oral squamous carcinoma. There is little information on the expression of HPV and its predictive markers in tumours of the major and minor salivary glands of the head and neck. We therefore assessed oral salivary gland neoplasms to identify associations between HPV and infection-related epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitor 2A (CDKN2A/p16) and tumour protein p53 (TP53). Formalin-fixed, paraffin-embedded tissue samples from oral salivary gland carcinomas (n=51) and benign tumours (n=26) were analysed by polymerase chain reaction (PCR) analysis for several HPV species, including high-risk types 16 and 18. Evaluation of EGFR, CDKN2A, TP53 and cytomegalovirus (CMV) was performed by immunohistochemistry. Epstein-Barr virus (EBV) was evaluated by EBV-encoded RNA in situ hybridisation. We demonstrated that salivary gland tumours are not associated with HPV infection. The expression of EGFR, CDKN2A and TP53 may be associated with tumour pathology but is not induced by HPV. CMV and EBV were not detectable. In contrast to oral squamous cell carcinomas, HPV, CMV and EBV infections are not associated with malignant or benign neoplastic lesions of the salivary glands.International Journal of Oral Science advance online publication, 11 July 2014; doi:10.1038/ijos.2014.28.
    International Journal of Oral Science 07/2014; 7(1). DOI:10.1038/ijos.2014.28 · 2.03 Impact Factor
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    ABSTRACT: Mutations in the cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC) genes are associated with an elevated risk for chronic pancreatitis, which is a known risk factor for pancreatic cancer (PC). Therefore, we analyzed whether PRSS1, CFTR, SPINK1, and/or CTRC mutations are associated with pancreatic adenocarcinoma.
    Pancreas 07/2014; DOI:10.1097/MPA.0000000000000166 · 3.01 Impact Factor
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    ABSTRACT: Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO EC-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LN) only. 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4xE90C600 q3w followed by 4xdocetaxel100 q3w (n=1008) to current standard: 6xF500E100C500 q3w (n=828) or C600M40F600 d1, 8 q4w (n=175). Primary endpoint was event-free survival (EFS); secondary endpoints were overall survival (OS), toxicity, translational research, and quality of life (QoL). Central tumor bank samples were evaluable in a representative collective (n=772; 40%). Ki-67 was assessed centrally in hormone receptor positive disease as surrogate marker for distinction of luminal A/B-like tumors. Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59 months median follow-up, superior efficacy of EC-Doc (vs. FEC) was seen in EFS and OS: 5-y EFS: 89.8% vs. 87.3% (p=0.038); 5-y OS: 94.5 vs. 92.8% (p=0.034); both tests one-tailed. EC-Doc caused more toxicity. In HR+ disease, only high-Ki-67 tumors (>20%) derived significant benefit from taxane-based therapy: hazard ratio=0.39 (95% CI: 0.18-0.82) for EC-Doc vs. FEC (test for interaction; p=0.01). EC-Doc significantly improved EFS and OS vs. FEC in intermediate-risk BC (1-3 LN) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.
    Annals of Oncology 05/2014; 25(8). DOI:10.1093/annonc/mdu186 · 6.58 Impact Factor

Publication Stats

6k Citations
1,305.69 Total Impact Points

Institutions

  • 2000–2015
    • Hannover Medical School
      • • Institute for Pathology
      • • Department of Paediatric Haematology and Oncology
      Hanover, Lower Saxony, Germany
  • 2002–2007
    • Hochschule Hannover
      Hanover, Lower Saxony, Germany
  • 1996–1997
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany