Gert Auer

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (216)756.05 Total impact

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    ABSTRACT: Immunohistochemical analysis of proliferation markers such as Ki-67 and cyclin A is widely used in clinical evaluation as a prognostic factor in breast cancer. The proliferation status of tumors is guiding the decision of whether or not a patient should be treated with chemotherapy because low-proliferative tumors are less sensitive by such treatment. However, the lack of optimal cutoff points and selection of tumor areas hamper its use in clinical practice. This study was performed to compare the Ki-67 and cyclin A expression counted in hot-spot vs average counting based on 5 to 14 random tumor areas in 613 breast carcinomas. We correlated the findings with 10-year follow-up in order to standardize the evaluation of proliferation markers in clinical practice. A significant correlation was found between the percentage of positive cells estimated by Ki-67 and cyclin A both by hot-spot and by average counting. Both methods showed that high expression of Ki-67 and cyclin A is associated with more adverse tumor stage. The cutoff value for Ki-67 for distant metastases was set to 22% and to 15%, using hot-spot and average counting, respectively. For cyclin A, the values were set to 14% and 8% using the respective methods. Survival curves revealed that patients with a high hot-spot proliferation index had a significantly greater risk of shorter tumor-free survival. Our findings suggest that the determination of proliferation markers in breast cancer should be standardized to hot-spot counting and that specific cutoff values for proliferation could be useful as prognostic markers in clinical practice. Moreover, we suggest that expression levels of cyclin A could be used as a complementary marker to estimate the proliferation status in tumors, especially those with "borderline" expression levels of Ki-67, in order to more accurately estimate the proliferations status of the tumors. Copyright © 2015. Published by Elsevier Inc.
    Annals of Diagnostic Pathology 05/2015; DOI:10.1016/j.anndiagpath.2015.05.002 · 1.11 Impact Factor
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    ABSTRACT: A previous study showed that regular use of low-dose aspirin was associated with smaller tumour size and fewer metastases for colorectal and lung cancer. We aim to explain these distinct effects in terms of the anti-inflammatory and anti-thrombotic properties of aspirin. From the Swedish Cancer Register, we identified patients diagnosed with colorectal and lung cancers between 1st October 2006 and 31st December 2009; each cancer was assessed in terms of tumour size/extent (T), lymph-node (N) and metastatic (M) status. Linkage with the Swedish Prescribed Drug Register was performed to obtain information on the use of low-dose aspirin, anti-inflammatory and anti-thrombotic drugs prior to cancer diagnosis. We identified 14,743 individuals with colorectal cancer and 5888 with lung cancer. For low-dose aspirin users we observed a statistically significant association with smaller tumour size and fewer metastases. For both cancers, the use of non-aspirin anti-inflammatory drugs was associated with smaller tumour size in all categories T2-T4 odds ratio (OR=0.76, 95% confidence interval (CI) 0.63-0.92 for T2 versus T1 in colorectal cancer), but not with metastatic status (OR=0.94, 95% CI 0.84-1.06 in colorectal cancer). In contrast, anti-thrombotic drug use was associated with fewer metastases, but not with tumour categories T2 and T3. The results suggest that the use of anti-inflammatories is associated with tumour-growth inhibition at the primary site, while the use of anti-thrombotics is associated with restriction of cancer-cell metastasising capability. These have clinical implications on the potential use of these drugs for chemoprevention or chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 02/2015; 51(6). DOI:10.1016/j.ejca.2015.02.004 · 4.82 Impact Factor
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    ABSTRACT: Anticoagulant treatment might enhance the natural defense against tumor cell dissemination caused by diagnostic needle biopsy by counteracting thrombocyte coating of such cells. To clarify whether women using anticoagulant treatment at the time of biopsy have a lower occurrence of lymph node metastasis, we conducted a nationwide Swedish cohort study of 26,528 female incident breast cancer patients in 2006 -2011. Point risk ratio (RR) of risk of lymph node metastasis among users of anticoagulant treatment adjusted for adjusted for age, T-stage, socioeconomic factors and concomitant medication was RR=0.94, 95% CI: 0.87-1.03), and lower in younger women (RR=0.80, 95% CI 0.50-1.29). Although non-significant, these associations may underestimate a true negative association since women using anticoagulant treatment are likely to have more concomitant diseases, lead an unhealthier lifestyle, and have lower participation in mammography screening. These findings provide some support for the hypothesis that anticoagulant medications might counteract breast cancer spread caused by needle biopsy. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 07/2014; 135(1). DOI:10.1002/ijc.28671 · 5.01 Impact Factor
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    ABSTRACT: Fluorescence nanoscopy provides means to discern the finer details of protein localization and interaction in cells by offering an order of magnitude higher resolution than conventional optical imaging techniques. However, these super resolution techniques put higher demands on the optical system as well as on the fluorescent probes, making multicolor fluorescence nanoscopy a challenging task. Here we present a new and simple procedure which exploits the photostability and excitation spectra of dyes to increase the number of simultaneous recordable targets in STED nanoscopy. We use this procedure to demonstrate four color STED imaging of platelets with ≤ 40 nm resolution and low crosstalk. Platelets can selectively store, sequester and release a multitude of different proteins, and in a manner specific for different physiological and disease states. By applying multicolor nanoscopy to study platelets, we can achieve spatial mapping of the protein organization with a high resolution, for multiple proteins at the same time and in the same cell. This provides a means to identify specific platelet activation states for diagnostic purposes and to understand the underlying protein storage and release mechanisms. We studied the organization of the pro- and anti-angiogenic proteins VEGF and PF-4 together with fibrinogen and filamentous actin, and found distinct features in their respective protein localization. Further, colocalization analysis revealed only minor overlap between the proteins VEGF and PF-4 indicating that they have separate storage and release mechanisms, corresponding well with their opposite roles as pro- and anti-angiogenic proteins, respectively.
    ACS Nano 04/2014; 8(5). DOI:10.1021/nn406113m · 12.03 Impact Factor
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    ABSTRACT: The objective of this study was to assess efficacy and safety of percutaneous ultrasound (US) guided preferential radiofrequency ablation (PRFA) in early breast carcinoma under local anesthesia and to evaluate a new assessment protocol. Eighteen breast cancer patients were enrolled in order to receive PRFA treatment three weeks prior to resection. Pain assessment was performed using the visual analoge scale. Analysis of treatment success was performed using magnetic resonance imaging (MRI) as well as histological assays for hematoxylin & eosin (H&E) and cytokeratine 8 (CK8). In a subset of patients contrast enhanced ultrasound (CEUS) was performed before and after treatment. MRI showed no residual tumor growth in 100% (18/18) of cases. Complete tumor devitalization was indicated in 83% (15/18) of patients as judged by H&E staining and in 89% (16/18) as judged by immunostaining for CK8. In 100% (18/18) at least one histologic method showed devitalization in the entire tumor. Treatment was well tolerated. Pain experienced during the procedure was mild. US-guided PRFA of small breast carcinoma is feasible under local anesthesia. MRI and CK8 have proven valuable additions to the RF breast tumor ablation protocol. CEUS shows potential as a modality for radiological follow-up.
    Breast (Edinburgh, Scotland) 04/2014; 23(2). DOI:10.1016/j.breast.2013.12.007 · 2.58 Impact Factor
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    ABSTRACT: The extent of epithelial cellular material (ECM) occurring in venous blood samples after diagnostic core needle biopsy (CNB) was studied in 23 patients with CNB diagnosed prostate cancer without provable metastases and 15 patients without cancer. The data show a significant increase of ECM in the peripheral blood sampled 20 seconds or 30 minutes after the last of 10 CNB procedures compared to the number of ECM detectable in the blood samples taken before the performance of CNB. The data indicate that diagnostic CNB of prostate cancer causes an extensive tissue trauma with a potential risk of cancer cell dissemination.
    Disease markers 01/2014; 2014:707529. DOI:10.1155/2014/707529 · 2.17 Impact Factor
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    ABSTRACT: Chromosomal aneuploidy has been identified as a prognostic factor in the majority of sporadic carcinomas. However, it is not known how chromosomal aneuploidy affects chromosome-specific protein expression in particular, and the cellular proteome equilibrium in general. The aim was to detect chromosomal aneuploidy-associated expression changes in cell clones carrying trisomies found in colorectal cancer. We used microcell-mediated chromosomal transfer to generate three artificial trisomic cell clones of the karyotypically stable, diploid, yet mismatch-deficient, colorectal cancer cell line DLD1 - each of them harboring one extra copy of either chromosome 3, 7 or 13. Protein expression differences were assessed by two-dimensional gel electrophoresis and mass spectrometry, compared to whole-genome gene expression data, and evaluated by PANTHER classification system and Ingenuity Pathway Analysis (IPA). In total, 79 differentially expressed proteins were identified between the trisomic clones and the parental cell line. Up-regulation of PCNA and HMGB1 as well as down-regulation of IDH3A and PSMB3 were revealed as trisomy-associated alterations involved in regulating genome stability. These results show that trisomies affect the expression of genes and proteins that are not necessarily located on the trisomic chromosome, but reflect a pathway-related alteration of the cellular equilibrium.
    Analytical cellular pathology (Amsterdam) 01/2014; 36(5-6). DOI:10.3233/ACP-140088 · 1.76 Impact Factor
  • Molecular Cancer Research 10/2013; 11(10 Supplement):A046-A046. DOI:10.1158/1557-3125.ADVBC-A046 · 4.50 Impact Factor
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    ABSTRACT: Abstract Context: Biological material reflecting the in vivo composition of markers provides a high potential for biomarker discovery. Objective: We compared the serum proteome following heat- and nitrogen-preservation, with and without subsequent storage at room temperature. Materials and methods: Serum samples were collected, treated and analysed by two-dimensional gel electrophoresis. Protein spots were identified and confirmed by two mass spectrometry approaches (MALDI & ESI) and subjected to Ingenuity Pathway Analysis. Results: We revealed 24 differentially expressed proteins (p ≤ 0.05) between nitrogen and heat preservation, and 87 between nitrogen and heat preservation with subsequent storage for 120 h at room-temperature. Mass spectrometry identified 25 polypeptides. Pathway analysis resulted in networks maintaining Cellular Assembly and Organization, Movement and Maintenance. Conclusion: Heat-stabilization does not substantially change the short-term proteome composition of serum compared with nitrogen treatment. However, heat-stabilization alone seems insufficient for long-term sample preservation for serum samples. We identified transthyretin and apolipoprotein A-IV as sample quality markers.
    Archives of Physiology and Biochemistry 07/2013; DOI:10.3109/13813455.2013.806556
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    ABSTRACT: BACKGROUND: CRIP1 (cysteine-rich intestinal protein 1) has been found in several tumor types, its prognostic impact and its role in cellular processes, particularly in breast cancer, are still unclear. METHODS: To elucidate the prognostic impact of CRIP1, we analyzed tissues from 113 primary invasive ductal breast carcinomas using immunohistochemistry. For the functional characterization of CRIP1, its endogenous expression was transiently downregulated in T47D and BT474 breast cancer cells and the effects analyzed by immunoblotting, WST-1 proliferation assay and invasion assay. RESULTS: We found a significant correlation between CRIP1 and HER2 (human epidermal growth factor receptor 2) expression levels (p = 0.016) in tumor tissues. In Kaplan Meier analyses, CRIP1 expression was significantly associated with the distant metastases-free survival of patients, revealing a better prognosis for high CRIP1 expression (p = 0.039). Moreover, in multivariate survival analyses, the expression of CRIP1 was an independent negative prognostic factor, along with the positive prognosticators nodal status and tumor size (p = 0.029). CRIP1 knockdown in the T47D and BT474 breast cancer cell lines led to the increased phosphorylation of MAPK and Akt, to the reduced phosphorylation of cdc2, and to a significantly elevated cell proliferation in vitro (p < 0.001). These results indicate that reduced CRIP1 levels may increase cell proliferation and activate cell growth. In addition, CRIP1 knockdown increased cell invasion in vitro. CONCLUSIONS: Because the lack of CRIP1 expression in breast cancer tissue is significantly associated with a worse prognosis for patients and low endogenous CRIP1 levels in vitro increased the malignant potential of breast cancer cells, we hypothesize that CRIP1 may act as a tumor suppressor in proliferation and invasion processes. Therefore, CRIP1 may be an independent prognostic marker with significant predictive power for use in breast cancer therapy.
    Molecular Cancer 04/2013; 12(1):28. DOI:10.1186/1476-4598-12-28 · 5.40 Impact Factor
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    ABSTRACT: BACKGROUND:: Malignant transformation in ulcerative colitis (UC) is associated with pronounced chromosomal instability, reflected by aneuploidy. Although aneuploidy can precede primary cancer diagnosis in UC for more than a decade, little is known of its cellular consequences. METHODS:: Whole-genome gene expression analysis was applied to noninflamed colon mucosa, mucosal biopsies of patients with UC, and UC-associated carcinomas (UCCs). DNA image cytometry was used to stratify samples into ploidy types. Differentially expressed genes (DEGs) were analyzed by Ingenuity Pathway Analysis and validated by real-time quantitative PCR. RESULTS:: Gene expression changes were more pronounced between normal mucosa and UC (2587 DEGs) than between UC and UCC (827 DEGs). Cytometry identified colitis patients with euploid or aneuploid mucosa biopsies, whereas all UCCs were aneuploid. However, 1749 DEGs distinguished euploid UC and UCCs, whereas only 15 DEGs differentiated aneuploid UC and UCCs. A total of 16 genes were differentially expressed throughout the whole sequence from normal controls to UCCs. Particularly, genes pivotal for chromosome segregation (e.g., SMC3 and NUF2) were differentially regulated along aneuploidy development. CONCLUSIONS:: The high number of DEGs between normal mucosa and colitis is dominated by inflammatory-associated genes. Subsequent acquisition of aneuploidy leads to subtle but distinct transcriptional alterations, revealing novel target genes that drive genomic instability and thus carcinogenesis. The gene expression signature of malignant phenotypes in aneuploid UC suggests that these lesions might need to be considered as severe as high-grade dysplasia.
    Inflammatory Bowel Diseases 02/2013; DOI:10.1097/MIB.0b013e31827eeaa4 · 5.48 Impact Factor
  • Biophysical Journal 01/2013; 104(2):342-. DOI:10.1016/j.bpj.2012.11.1900 · 3.83 Impact Factor
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    ABSTRACT: Background There is evidence that the extent of the G2/M arrest following irradiation is correlated with tumour cell survival and hence therapeutic success. We studied the regulation of cellular response to radiation treatment by miR-21-mediated modulation of cell cycle progression in breast cancer cells and analysed miR-21 expression in breast cancer tissue samples with long-term follow up. Methods The miR-21 expression levels were quantified (qRT-PCR) in a panel of 86 cases of invasive breast carcinomas in relation to metastasis free survival. The cellular radiosensitivity of human breast cancer cells after irradiation was determined comparing two cell lines (T47D and MDA-MB-361) by cell proliferation and colony forming assays. The influence of miR-21 overexpression or downregulation on cell cycle progression and G2/M checkpoint arrest after irradiation was assessed by flow cytometric analysis. Results The expression of miR-21 was transiently increased 8 hours after irradiation in the radioresistant T47D cells and significantly changed with lower extent in radiosensitive MDA-MB-361 cells. Anti-miR-21 treated breast cancer cells failed to exhibit the DNA damage-G2 checkpoint increase after irradiation. Apoptotic activity was significantly enhanced from 7% to 27% in T47D cells and from 18% to 30% in MDA-MB-361 cells 24 hours after 5 Gy irradiation. Additionally, we characterized expression of miR-21 in invasive breast carcinomas. In comparison to non-cancerous adjacent breast tissue, tumours samples had increased miR-21 expression that inversely correlated with the distant metastases-free survival of patients (p = 0.029). Conclusions Our data indicate that miR-21 expression in breast cancer cells contributes to radiation resistance by compromising cell cycle progression. These data point to the potential of combining radiotherapy with an anti-miR-21 as a potent G2/M check point inhibitor in overcoming radiation resistance of tumours.
    Radiation Oncology 12/2012; 7(1):206. DOI:10.1186/1748-717X-7-206 · 2.36 Impact Factor
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    ABSTRACT: OBJECTIVE: This study aimed to analyze the prognostic value of DNA content and biological markers for cell cycle regulation and invasion in primary carcinoma of the vagina (PCV). MATERIAL AND METHODS: Seventy-two consecutive patients with PCV, categorized as short-term (≤2 years) and long-term (≥8 years) survivors, were evaluated for DNA content by image cytometry, and for expression of p53, p21, cyclin A, Ki67, E-cadherin, and laminin-5γ2 chain by immunohistochemistry. The relationship between these biological markers and histopathological and clinical parameters was assessed. RESULTS: All PCV showed aneuploid DNA content. Most of the PCV patients showed no overexpression of p53 and high expression of p21, cyclin A, and Ki67. Loss or underexpression of E-cadherin was found in 94% (68/72) of PCV patients, and all patients showed immunopositivity for the laminin-5γ2 chain. Tumors with a vaginal longitudinal location in the lower third or in the entire vagina more often had overexpression of p53, high expression of Ki67 (P = 0.044), and underexpression of E-cadherin (P = 0.038), than tumors confined only to the upper third. Overexpression of p53 was significantly associated with short-term survival in the univariate analysis, but not in the multivariate analysis adjusted for age at diagnosis and tumor size. CONCLUSIONS: The expression level of some markers was related to tumor location, which might be indicative of different genesis. Overexpression of p53 was associated with short-term survival, but the only independent predictors of survival were age at diagnosis and tumor size.
    International Journal of Gynecological Cancer 11/2012; 23(1). DOI:10.1097/IGC.0b013e31827670c4 · 1.95 Impact Factor
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    ABSTRACT: Dysregulation of how platelets store, sequester and release specific proteins seems to be implicated in many disease states, including cancer. Dual-color immunofluorescence stimulated emission depletion (STED) microscopy with 40 nm resolution is used to map pro-angiogenic VEGF, anti-angiogenic PF-4 and fibrinogen in >300 individual platelets. This reveals that these proteins are stored in a segmented, zonal manner within regional clusters, significantly smaller than the size of an α-granule. No colocalization between the different proteins is observed. Upon platelet activation by thrombin or ADP, the proteins undergo significant spatial rearrangements, including alterations in the size and number of the protein clusters, and specific for a certain protein and the type of activation induced. Following these observations, a simple assignment procedure is used to show that the three distinct states of platelets (non-, ADP- and thrombin-activated) can be identified based on the average size, number and peripheral localization profiles of the regional protein clusters within the platelets. Thus, high-resolution spatial mapping of specific proteins is a useful procedure to detect and characterize deviations in the selective storage, release and uptake of these proteins in the platelets. Since these deviations seem to be specific for, and may even underlie, certain patophysiological states, these findings may have interesting diagnostic and therapeutic implications.
    11/2012; 1(6):707-13. DOI:10.1002/adhm.201200172
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    ABSTRACT: To study elderly women > or = 60 years of age diagnosed with breast cancer and analyze this cohort according to death from breast cancer and death due to comorbidities. Patients aged 60-69 years of age were included in routine mammography screening, but not women aged > or = 70 years. This enabled a comparison between the 2 groups regarding screening effect, tumor size and survival in breast cancer. A consecutive sample of 311 breast cancer patients > or = 60 years of age from 1991 were analyzed according to tumor size at diagnosis, frequencies of lymph node metastasis, tumor histological grade and stage, ploidy, proliferation index, stem-line-scatter index and survival rate in breast cancer and other causes of death. Tumor size was compared to a patient group aged 60-69 from 1987, before the introduction of mammography screening in Sweden. In the screening group a significant reduction in tumor size was found at diagnosis compared to the sample from 1987 (p < 0.001) and to the older group > or = 70 years (p < 0.02). In the latter group a higher death rate appeared for breast cancer. Older women would have a better outcome if included in the mammography screening program.
    Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 08/2012; 34(4):189-94. · 0.58 Impact Factor

Publication Stats

5k Citations
756.05 Total Impact Points

Institutions

  • 1986–2015
    • Karolinska Institutet
      • • Department of Oncology-Pathology
      • • Cancer Center Karolinska - CCK
      • • Department of Medical Biochemistry and Biophysics
      Solna, Stockholm, Sweden
  • 1983–2014
    • Karolinska University Hospital
      • • Cancer Center Karolinska (CCK)
      • • Department of Oncology
      • • Gynecology Unit
      • • Department of Obstetrics and Gynecology
      Tukholma, Stockholm, Sweden
  • 2009
    • National Cancer Institute (USA)
      • Chemical Biology Laboratory
      Maryland, United States
  • 2007
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 2006
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2004
    • University of Oulu
      • Department of Biochemistry
      Uleoborg, Northern Ostrobothnia, Finland
  • 1993
    • St. Franziskus-Hospital
      Köln, North Rhine-Westphalia, Germany
  • 1989
    • Uppsala University Hospital
      • Department of Clinical Pathology and Cytology
      Uppsala, Uppsala, Sweden
  • 1988
    • Englewood Hospital and Medical Center
      Englewood, New Jersey, United States
  • 1986–1987
    • City of Stockholm
      Tukholma, Stockholm, Sweden