Katja Specht

Technische Universität München, München, Bavaria, Germany

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Publications (54)316.33 Total impact

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    ABSTRACT: Purpose To evaluate utility of magnetic resonance (MR) imaging in local staging of soft-tissue sarcoma, with an emphasis on assessment of neurovascular encasement. Materials and Methods Institutional review board approval was obtained; informed consent requirement was waived. Preoperative MR images in 174 patients with soft-tissue sarcoma were analyzed by two readers. Tumor staging according to the American Joint Committee on Cancer/Union International Contre le Cancer and Enneking staging systems and analysis of osseous and articular invasion were performed. To assess neurovascular encasement, contact between tumor and arteries, between tumor and veins, and between tumor and nerves was classified (no contact, contact ≤90°, 91°-180°, 181°-270°, >271°). Interobserver agreement was determined; imaging findings were correlated with intraoperative findings and/or histopathologic findings (Pearson correlation coefficient [r] and Cohen κ coefficient). Results Intraoperative evaluation and/or histopathologic evaluation confirmed osseous, articular, and neurovascular invasion in 8.6%, 2.9%, and 25.3% of patients. Interobserver agreement was excellent for tumor staging (American Joint Committee on Cancer/Union International Contre le Cancer staging, κ = 0.811; Enneking staging, κ = 0.943) and osseous invasion (κ = 1.000). It was substantial for articular invasion (κ = 0.794). Sensitivity and specificity for osseous invasion were 100% and 98.7%, respectively (both readers). For articular invasion, sensitivity was 80% (both readers); specificities were 100% and 98.8% for readers 1 and 2, respectively. Interobserver agreement in quantifying contact between tumor and vessels and between tumor and nerves was excellent for arteries, veins, and nerves (κ = 0.845, 0.892, 0.893, respectively). Receiver operating characteristic analysis revealed optimal threshold of greater than 180° for prediction of arterial and venous encasement (both readers). For neural encasement, optimal threshold was greater than 180° (reader 1) and greater than 270° (reader 2). Sensitivities in diagnosing encasement for arteries, veins, and nerves were 84.6%, 84.6%, and 77.8% (reader 1) and 84.6%, 84.6%, and 72.2% (reader 2). Specificities for encasement of arteries, veins, and nerves, respectively, were 97.5%, 97.5%, and 93.2% (reader 1) and 93.8%, 94.7%, 97.3% (reader 2). Conclusion MR imaging allows reliable and accurate local staging of soft-tissue sarcoma. Encasement of arteries, veins, and nerves should be diagnosed, if the contact between tumor and vascular or neural circumference exceeds 180°. (©) RSNA, 2015 Online supplemental material is available for this article.
    Radiology 01/2015; DOI:10.1148/radiol.14140510 · 6.21 Impact Factor
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    ABSTRACT: Detection of anaplastic lymphoma kinase (ALK)-gene rearrangements in non-small-cell lung cancer (NSCLC) is mainly performed by fluorescence in-situ hybridization (FISH). The question was raised if FISH might be replaced by immunohistochemistry (IHC) in a reliable and reproducible manner across different laboratories. After calibration of the staining instruments and training of the observers to binary interpretation (positive versus negative), 15 NSCLC were independently tested for ALK protein expression by IHC only in a multicenter setting (16 institutes). Each laboratory utilized the VENTANA ALK-D5F3 IHC assay. As demonstrated by FISH the samples displayed unequivocal ALK break-positivity (6×) and negativity (7×), as well as ALK positive-"borderline" character (2×), which is challenging for FISH diagnosis and thus was RT-PCR-confirmed. All seven ALK FISH-negative cases were homogenously scored as ALK-IHC negative. All 16 participants scored the two ALK positive-"borderline" samples as unequivocally positive according to their protein expression. Concordant IHC interpretation was also noticed in four of six unequivocal ALK break positive cases. In two of six some observers described a weak/heterogeneous ALK-IHC staining. This would have resulted in a subsequent ALK-testing (FISH/PCR) in a routine diagnostic setting. This so-called "ALK-Harmonization-Study" shows for the first time that predictive semiquantitative IHC reveals reliable and reproducible results across several labs when methodology and interpretation are strictly defined and the pathologists are uniquely trained. The application of validated ALK IHC assays and its comparison to ALK-FISH is highly needed in future clinical trials. This might answer the question if ALK-IHC cannot only serve as a prescreening tool, but as a stand-alone test at least in cases displaying an unequivocally staining pattern as well as an alternative predictive test in samples with reduced FISH interpretability.
    Journal of Thoracic Oncology 11/2014; 9(11):1685-1692. DOI:10.1097/JTO.0000000000000332 · 5.80 Impact Factor
  • Geburtshilfe und Frauenheilkunde 09/2014; 74(S 01). DOI:10.1055/s-0034-1388437 · 0.96 Impact Factor
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    ABSTRACT: The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic (k w) = 0.73 (95 % confidence interval (CI), 0.41-0.94)), with a higher agreement between the reference evaluation and the PFPE samples (k w = 0.86 (95 % CI, 0.67-1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory (k w = 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.
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    ABSTRACT: OBJECTIVES: To test the hypothesis that bone marrow oedema (BME) observed on MRI in patients with avascular necrosis (AVN) of the femoral head represents an indicator of subchondral fracture. METHODS: Thirty-seven symptomatic hips of 27 consecutive patients (53 % women, mean age 49.2) with AVN of the femoral head and associated BME on magnetic resonance (MR) imaging were included. MR findings were correlated with computed tomography (CT) of the hip and confirmed by histopathological examination of the resected femoral head. Imaging studies were analysed by two radiologists with use of the ARCO classification. RESULTS: On MR imaging a fracture line could be identified in 19/37 (51 %) cases, which were classified as ARCO stage 3 (n = 15) and stage 4 (n = 4). The remaining 18/37 (49 %) cases were classified as ARCO stage 2. However, in all 37/37 (100 %) cases a subchondral fracture was identified on CT, indicating ARCO stage 3/4 disease. The extent of subchondral fractures and the femoral head collapse was graded higher on CT as compared to MRI (P < 0.05). Histopathological analysis confirmed bone necrosis and subchondral fractures. CONCLUSIONS: In patients with AVN, BME of the femoral head represents a secondary sign of subchondral fracture and thus indicates ARCO stage 3 disease.
    European Radiology 05/2014; 24(9). DOI:10.1007/s00330-014-3216-8 · 4.34 Impact Factor
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    ABSTRACT: Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of the bile duct from 45 patients were graded and subtyped using mucin markers and CDX2. In addition, tumors were analyzed for common oncogenic pathways, and the findings were correlated with subtype and grade. Data were compared with those from 22 extra- and intrahepatic cholangiocarcinomas. Intraductal papillary neoplasms showed a development from preinvasive low- to high-grade intraepithelial neoplasia to invasive carcinoma. Molecular and immunohistochemical analysis revealed mutated KRAS, overexpression of TP53 and loss of p16 in low-grade intraepithelial neoplasia, whereas loss of SMAD4 was found in late phases of tumor development. Alterations of HER2, EGFR, β-catenin and GNAS were rare events. Among the subtypes, pancreato-biliary (36%) and intestinal (29%) were the most common, followed by gastric (18%) and oncocytic (13%) subtypes. Patients with intraductal papillary neoplasm of the bile duct showed a slightly better overall survival than patients with cholangiocarcinoma (hazard ratio (cholangiocarcinoma versus intraductal papillary neoplasm of the bile duct): 1.40; 95% confidence interval: 0.46-4.30; P=0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenoma-carcinoma sequence that correlates with the stepwise activation of common oncogenic pathways. Further large trials are needed to investigate and verify the finding of a better prognosis of intraductal papillary neoplasms compared with conventional cholangiocarcinoma.Modern Pathology advance online publication, 5 July 2013; doi:10.1038/modpathol.2013.112.
    Modern Pathology 07/2013; DOI:10.1038/modpathol.2013.112 · 6.36 Impact Factor
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    ABSTRACT: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor specific CKIT or PDGFRA mutant DNA fragments can be detected and quantified in plasma samples of GIST patients. We prospectively collected 291 plasma samples from 38 subjects with GIST harbouring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific Ligation PCR to detect mutant free circulating (fc)DNA. We were able to detect fcDNA harbouring the tumor mutation in 15 out of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared to patients in CR. The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations, and found four additional exchanges, including mutations not known from sequentially performed tumor biopsies. Our results indicate that free circulating DNA harbouring tumor specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies.
    Clinical Cancer Research 07/2013; 19(17). DOI:10.1158/1078-0432.CCR-13-0765 · 8.19 Impact Factor
  • Annals of Hematology 06/2013; 93(3). DOI:10.1007/s00277-013-1814-1 · 2.40 Impact Factor
  • Senologie - Zeitschrift für Mammadiagnostik und -therapie 06/2013; 10(02). DOI:10.1055/s-0033-1347567
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    ABSTRACT: OBJECTIVE: Primary hepatic angiosarcoma is a very rare and aggressive malignancy of vascular origin. We describe cross-sectional imaging findings of this entity with emphasis on dynamic contrast-enhanced (DCE) and diffusion-weighted (DWI) MR imaging. METHODS: Seven cases of pathologically confirmed hepatic angiosarcoma were retrospectively reviewed (CT and MRI examinations were available in seven and six patients, respectively). Two radiologists evaluated lesion growth patterns, attenuation, signal intensity characteristics, contrast enhancement patterns, and apparent diffusion coefficients (ADCs). RESULTS: Multifocal hepatic disease was present in six patients by means of a mixed pattern of large dominant masses and multiple small nodules; one patient had a solitary large mass. Unenhanced images depicted hemorrhagic areas and a markedly heterogeneous internal architecture within large tumors. Contrast-enhanced early phase images showed variable patterns including patchy peripheral or bizarre shaped intralesional foci of enhancement, peripheral rim enhancement, and small lesions without enhancement. On DCE images, the majority of lesions presented with varying degrees of progressive enhancement. Small nodules frequently displayed homogeneous enhancement on delayed phase images due to complete fill-in. DWI revealed a high interlesional variability of ADC values (range 0.57-2.41 × 10(-3 )mm(2)/s, mean 1.37 × 10(-3 )mm(2)/s). CONCLUSION: Cross-sectional imaging findings of hepatic angiosarcoma reflect the varied histopathological composition of the tumors. Multifocal disease, hemorrhage within large lesions, as well as progressive enhancement on DCE images are typical features of hepatic angiosarcoma. The mean ADC of lesions was found to be slightly elevated in comparison with other hepatic malignancies.
    Abdominal Imaging 12/2012; 38(4). DOI:10.1007/s00261-012-9967-2 · 1.91 Impact Factor
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    ABSTRACT: Objectives Ovarian borderline tumors (BOTs) generally have an excellent prognosis, although recurrences and malignant transformation can occur. Our aim was to compare clinicopathologic features of BOT with clinical outcome.Methods In seventy consecutive BOTs clinicopathologic parameters, tumor cell proliferation (Ki67) and in selected cases KRAS, BRAF and p53 mutational status were analyzed with recurrence-free and overall survival as the endpoints.ResultsSixty-one (87%) patients presented with FIGO stage I, 3 stage II, and 6 stage III. Thirty-four patients had serous and 36 mucinous BOT (30 intestinal and 6 endocervical subtypes). Non-invasive peritoneal implants occurred in 9 patients, and no invasive implants were observed. Recurrence-free and overall survival rates were 91% and 99%, respectively, at a mean follow-up of 63 months.Disease recurrence occurred in 6 cases (all FIGO stage I) including 3 serous, 1 mucinous-intestinal, and 2 mucinous-endocervical subtypes. Mean time to recurrence was 27 months (range 8–68). The recurrence rate following fertility-conserving surgery was 31% (5/16) compared to 2% (1/54) after bilateral salpingo-oophorectomy. Neither peritoneal implants (9/70), micropapillary pattern (2/34), microinvasion (4/70), nor increased tumor cell proliferation was associated with a higher recurrence rate. The frequency of KRAS or BRAF mutations was 50% (3/6 recurrences and 3/6 controls; 4 KRAS, 2 BRAF mutations). No p53 mutations (0/12) were detected in primary or recurrent BOTs.Conclusions Histopathologic parameters were not predictive of BOT recurrence including previously suggested risk factors such as micropapillary pattern and microinvasion. However, fertility-conserving surgery and incomplete surgical staging were associated with a higher risk for recurrence.
    Gynecologic Oncology 12/2012; 127(3):516–524. DOI:10.1016/j.ygyno.2012.08.027 · 3.69 Impact Factor
  • Senologie - Zeitschrift für Mammadiagnostik und -therapie 04/2012; 8(01):6-9. DOI:10.1055/s-0032-1312011
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    ABSTRACT: Gene expression profiles provide important information about the biology of breast tumors and can be used to develop prognostic tests. However, the implementation of quantitative RNA-based testing in routine molecular pathology has not been accomplished, so far. The EndoPredict assay has recently been described as a quantitative RT-PCR-based multigene expression test to identify a subgroup of hormone-receptor-positive tumors that have an excellent prognosis with endocrine therapy only. To transfer this test from bench to bedside, it is essential to evaluate the test-performance in a multicenter setting in different molecular pathology laboratories. In this study, we have evaluated the EndoPredict (EP) assay in seven different molecular pathology laboratories in Germany, Austria, and Switzerland. A set of ten formalin-fixed paraffin-embedded tumors was tested in the different labs, and the variance and accuracy of the EndoPredict assays were determined using predefined reference values. Extraction of a sufficient amount of RNA and generation of a valid EP score was possible for all 70 study samples (100%). The EP scores measured by the individual participants showed an excellent correlation with the reference values, respectively, as reflected by Pearson correlation coefficients ranging from 0.987 to 0.999. The Pearson correlation coefficient of all values compared to the reference value was 0.994. All laboratories determined EP scores for all samples differing not more than 1.0 score units from the pre-defined references. All samples were assigned to the correct EP risk group, resulting in a sensitivity and specificity of 100%, a concordance of 100%, and a kappa of 1.0. Taken together, the EndoPredict test could be successfully implemented in all seven participating laboratories and is feasible for reliable decentralized assessment of gene expression in luminal breast cancer.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 02/2012; 460(3):251-9. DOI:10.1007/s00428-012-1204-4 · 2.56 Impact Factor
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    ABSTRACT: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy. We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation. TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism. TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).
    New England Journal of Medicine 01/2012; 366(1):44-53. DOI:10.1056/NEJMoa1009473 · 54.42 Impact Factor
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    ABSTRACT: Hepatic epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with low- to intermediate-grade malignant potential. We describe cross-sectional imaging findings of pathologically confirmed EHE including preliminary observations on lesion characteristics and apparent diffusion coefficients (ADCs) at diffusion-weighted MR imaging (DWI). CT and MRI examinations in five patients were retrospectively reviewed. Two radiologists evaluated lesion growth patterns, attenuation, signal intensity characteristics, and contrast enhancement patterns. Additionally, DWI features on low and high b-value images as well as ADCs were assessed in three patients. Imaging features of EHE included multifocal hepatic disease (n = 5), predominantly subcapsular location (n = 5), coalescence of nodules (n = 5), capsular retraction (n = 3), and intralesional calcifications (n = 3). Contrast-enhanced CT and MR images showed variable degrees of peripheral rim enhancement. T2-weighted MR images, low b-value DWI and ADC maps frequently depicted a "target-sign" appearance of tumor nodules. A markedly hyperintense central area corresponding to hypocellular stroma was surrounded by a moderately hyperintense outer rim reflecting hypercellular tumor regions. The mean ADC of lesions was 1.86 × 10(-3) mm(2)/s. Cross-sectional imaging displayed typical features of EHE. The mean ADC value of lesions was found to be relatively high in comparison with other hepatic malignancies, which may be helpful in suggesting the diagnosis.
    Abdominal Imaging 08/2011; 36(4):415-24. DOI:10.1007/s00261-010-9641-5 · 1.91 Impact Factor
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    ABSTRACT: Human epidermal growth factor receptor 2 expression in osteosarcoma and its relationship to prognosis have been the subject of several conflicting reports, most of them relying on immunohistochemical studies. Because the urgent need of prognostic markers and effective new treatment options for osteosarcoma patients, we evaluated the role of human epidermal growth factor receptor 2 in 2 well-characterized sets of pretherapeutic osteosarcoma samples (46 paraffin-embedded and 46 fresh-frozen biopsy samples) using immunohistochemistry with 2 different antibodies [DAKO A0485 (Glostrup, Denmark) and Novocastra CB11 (Newcastle, UK)] as well as fluorescence in situ hybridization, real-time polymerase chain reaction, and SNP array analyses and correlated our findings with clinicopathological parameters. However, our study failed to detect unequivocal evidence of human epidermal growth factor receptor 2 gene amplification or overexpression of human epidermal growth factor receptor 2 messenger RNA or protein in any of the investigated tumors. Only in a small subset of samples, a moderate increase in messenger RNA levels (13.6%) or focal membranous immunoreactivity (8.7%; A0485) was detected but did not correlate with survival or response to chemotherapy. Cytoplasmic staining was identified more frequently (63%; CB11) but again did not show any association with clinicopathological parameters. In conclusion, our study does not support a role for human epidermal growth factor receptor 2 as a prognostic marker in osteosarcoma.
    Human pathology 02/2011; 42(6):859-66. DOI:10.1016/j.humpath.2010.09.016 · 2.81 Impact Factor
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    ABSTRACT: The aim of this study was to determine whether pretherapeutic protein expression levels of the excision repair cross-complementing (ERCC1) enzyme, thymidylate synthetase (TS), multidrug-resistance protein 1 (MRP-1) and P-glycoprotein (P-gp) are associated with tumour response to cisplatin and fluorouracil (5-FU)-based neoadjuvant chemotherapy in oesophageal adenocarcinomas. The expression levels of ERCC1, TS, MDR-1 and P-gp were determined immunohistochemically in pretherapeutic tumour biopsies from 40 oesophageal adenocarcinoma patients and were correlated with histopathological tumour regression and with patient survival. Protein expression was compared to mRNA data, which was previously published for ERCC1, TS and MRP-1 and newly determined for the purpose of this study for MDR-1/P-gp. High-TS and -MRP-1 protein expression was correlated with tumour non-response to chemotherapy (P = 0.001 and P = 0.036, respectively). For ERCC-1 and P-gp, no association between pretherapeutic protein expression and response was found. There was no correlation between mRNA levels and protein expression for all investigated markers. Survival analysis revealed a trend towards increased survival for low-ERCC-1 expression (P = 0.079). The pattern of pretherapeutic expression of TS and MRP-1 is related to chemotherapy response in oesophageal adenocarcinoma patients. Immunohistochemical assessment of these markers may be helpful for response prediction.
    Journal of Surgical Oncology 10/2010; 102(5):503-8. DOI:10.1002/jso.21641 · 2.84 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) overexpression and activation are hallmarks of non-small cell lung carcinoma (NSCLC). Although EGFR-targeted therapies are used, the prognosis of NSCLC remains poor. ADAM17 induces activation of the EGFR through ligand cleavage. However, we show that inhibition or knockdown of ADAM17 markedly reduces tumorigenesis and survival to a large part independently from EGFR ligand shedding in NSCLC cells. These findings strongly indicate additional oncogenic mechanisms regulated by ADAM17. We identified Notch1 signaling as an ADAM17-controlled pathway and a critical regulator of anchorage-independent growth by using both Notch1 shRNA and ectopic expression of the active intracellular Notch1 fragment. Strikingly, Notch1 knockdown led to a strong reduction of EGFR expression in all analyzed cell lines. Proliferation, survival, and colony formation of Notch1-deficient cells were insensitive to EGF stimulation. Moreover, targeting Notch1 or ADAM17 resulted in substantial cell death, whereas EGFR inhibition predominantly induced cell cycle arrest. Immunohistochemical analysis of primary human tissue revealed a significant correlation between ADAM17, Notch1 signaling, and high EGFR expression levels. In conclusion, this article describes a novel molecular circuitry in NSCLC, incorporating ADAM17 as a regulator of EGFR expression through the activation of Notch1. Due to their central role in tumorigenesis and survival of NSCLC cells, both ADAM17 and Notch1 constitute promising targets for the treatment of NSCLC.
    Cancer Research 07/2010; 70(13):5368-78. DOI:10.1158/0008-5472.CAN-09-3763 · 9.28 Impact Factor
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    ABSTRACT: Clinical laboratory testing for HER2 status in breast cancer tissues is critically important for therapeutic decision making. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating proteins through the direct and morphology-driven analysis of tissue sections. We hypothesized that MALDI-IMS may determine HER2 status directly from breast cancer tissues. Breast cancer tissues (n = 48) predefined for HER2 status were subjected to MALDI-IMS, and protein profiles were obtained through direct analysis of tissue sections. Protein identification was performed by tissue microextraction and fractionation followed by top-down tandem mass spectrometry. A discovery and an independent validation set were used to predict HER2 status by applying proteomic classification algorithms. We found that specific protein/peptide expression changes strongly correlated with the HER2 overexpression. Among these, we identified m/z 8404 as cysteine-rich intestinal protein 1. The proteomic signature was able to accurately define HER2-positive from HER2-negative tissues, achieving high values for sensitivity of 83%, for specificity of 92%, and an overall accuracy of 89%. Our results underscore the potential of MALDI-IMS proteomic algorithms for morphology-driven tissue diagnostics such as HER2 testing and show that MALDI-IMS can reveal biologically significant molecular details from tissues which are not limited to traditional high-abundance proteins.
    Journal of Proteome Research 02/2010; 9(4):1854-63. DOI:10.1021/pr901008d · 5.06 Impact Factor
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    ABSTRACT: To identify pretherapeutic predictive biomarkers in tumor biopsies of patients with locally advanced esophageal adenocarcinomas treated with neoadjuvant chemotherapy, we used an explorative proteomic approach to correlate pretherapeutic protein expression profiles with tumor response to neoadjuvant chemotherapy. Thirty-four patients with locally advanced esophageal adenocarcinomas who received neoadjuvant platin/5-fluorouracil-based chemotherapy before surgical resection were enrolled in this study. Response to chemotherapy was determined (a) by the amount of decline of [18F]fluorodeoxyglucose tumor uptake 2 weeks after the start of chemotherapy measured by positron emission tomography and (b) by histopathologic evaluation of tumor regression after surgical resection. Explorative quantitative and qualitative protein expression analysis was done through a quantitative differential protein expression analysis that used dual-isotope radioactive labeling of protein extracts. Selected identified biomarkers were validated by immunohistochemistry and quantitative real time reverse transcription-PCR. Proteomic analysis revealed four cellular stress response-associated proteins [heat-shock protein (HSP) 27, HSP60, glucose-regulated protein (GRP) 94, GRP78] and a number of cytoskeletal proteins whose pretherapeutic abundance was significantly different (P < 0.001) between responders and nonresponders. Immunohistochemistry and gene expression analysis confirmed these data, showing a significant association between low HSP27 expression and nonresponse to neoadjuvant chemotherapy (P = 0.049 and P = 0.032, respectively). Albeit preliminary, our encouraging data suggest that protein expression profiling may distinguish cancers with a different response to chemotherapy. Our results suggest that response to chemotherapy may be related to a different activation of stress response and inflammatory biology in general. Moreover, the potential of HSPs and GRPs as biomarkers of chemotherapy response warrants further validation.
    Clinical Cancer Research 12/2008; 14(24):8279-87. DOI:10.1158/1078-0432.CCR-08-0679 · 8.19 Impact Factor

Publication Stats

2k Citations
316.33 Total Impact Points

Institutions

  • 2003–2014
    • Technische Universität München
      • Institut für Allgemeine Pathologie und Pathologische Anatomie
      München, Bavaria, Germany
  • 2004
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 2002
    • Max Planck Institute of Biochemistry
      • Department of Molecular Biology
      München, Bavaria, Germany