Rosmarie Caduff

University of Zurich, Zürich, Zurich, Switzerland

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Publications (59)184.18 Total impact

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    ABSTRACT: Endometrial cancer is the most frequently occurring malignancy of the female genital tract in Western countries. Although in many cases surgically curable, about 30% of the tumors represent an aggressive and untreatable disease. In an attempt to establish a reliable prognostic marker for endometrial carcinomas disregarding their histological diversity, we investigated the expression of KPNA2, a mediator of nucleocytoplasmic transport, and other cell proliferation-associated proteins and their correlation with cancer progression. We analyzed patient tissue microarrays (TMAs) assembled from 527 endometrial cancer tissue specimens and uterus samples from a Trp53 knockout mouse model of endometrial cancer. Our data show that KPNA2 expression was significantly upregulated in human endometrial carcinomas and associated with higher tumor grade (p = 0.026), higher FIGO stage (p = 0.027), p53 overexpression (p < 0.001), activation of the PI3K-AKT pathway, and epithelial-mesenchymal transition. Increased nuclear KPNA2 immunoreactivity was identified as a novel predictor of overall survival, independent of well-established prognostic factors in Cox regression analyses (hazard ratio 1.7, 95%-CI 1.13-2.56, p = 0.01). No significant association between KPNA2 expression and endometrial cancer subtype was detected. In the mouse model, KPNA2 showed increased expression levels from precancerous (EmgD, EIC) to far advanced invasive lesions. We further investigated the cell proliferation capacity after siRNA-mediated KPNA2 knockdown in the human endometrial cancer cell line MFE-296. KPNA2 silencing led to decreased proliferation of the cancer cells suggesting interplay of the protein with the cell cycle. Taken together, increased expression of KPNA2 is an independent prognostic marker for poor survival. The mechanism of enhanced nucleo-cytoplasmic transport by KPNA2 overexpression seems a common event in aggressive cancers since we have shown a significant correlation of KPNA2 expression and tumor aggressiveness in a large variety of other solid tumor entities. Introducing KPNA2 immunohistochemistry in routine diagnostics may allow for the identification of patients who need more aggressive treatment regimens.
    The Journal of Pathology 06/2014; · 7.59 Impact Factor
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    ABSTRACT: Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting β-catenin dependent and independent Wnt signalling pathways.
    Gynecologic Oncology 06/2014; · 3.93 Impact Factor
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    ABSTRACT: Aims Epithelial ovarian cancer (EOC) can be classified into four major types (serous, endometrioid, clear cell, mucinous). The prevalence of driver gene mutations in the different subtypes is controversial. High-grade serous carcinomas show frequent TP53 mutations, whereas KRAS and BRAF mutations are less common. In non-serous EOC, the relevance of these gene mutations remains to be elucidated. We investigated 142 formalin-fixed, paraffin-embedded EOC, including serous (n=63), endometrioid (n=29), clear cell (n=25), mucinous (n=14), and others (n=11) for mutations in TP53 exons 5-8, KRAS exons 2 and 3, and BRAF exon 15 by pyro-sequencing using the GS Junior 454 platform. The mutational status was correlated with clinicopathological features and patient overall survival. We identified mutations in the coding region of TP53 in 51.4% (73/142), and of KRAS in 9.9% (14/142) but not of BRAF. TP53 mutations occurred frequently in high-grade serous carcinomas (58.7%), but also in mucinous (57%) and clear cell EOC (52%). TP53 mutations were associated with high-grade carcinomas (p=0.014), advanced FIGO stage (p=0.001), intraoperative residual disease >1cm (p=0.004), as well as poor overall survival (p=0.002). KRAS mutations were mainly identified in mucinous EOC (57%) and were concomitantly with TP53 mutations in five mucinous carcinomas (36%). TP53 gene driver mutations are a common feature of all advanced ovarian cancer subtypes, whereas BRAF mutations seem to be a rare event in EOC. KRAS mutations with synchronous TP53 mutations occur predominantly in low-grade mucinous carcinomas, suggesting a specific molecular background of this ovarian cancer type.
    Experimental and Molecular Pathology 08/2013; · 2.13 Impact Factor
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    ABSTRACT: Enteroviruses are a leading cause of viral infections in children. While most enteroviral infections are mild and self-limiting, severe disease such as a viral sepsis syndrome, myocarditis, hepatitis and meningoencephalitis may occur. We present two cases of neonatal enteroviral myocarditis. Cardiorespiratory failure occurred in both cases, and severe shock refractory to conventional treatment required support with extracorporeal membrane oxygenation (ECMO). One child with coxsackievirus B3 myocarditis failed to recover and died after 3 weeks on ECMO, while one child could be decannulated successfully after 9 days of ECMO and recovered completely subsequently. In conclusion, neonatal myocarditis has a very high mortality, and ECMO should be considered early in neonates with rapid clinical and echocardiographic deterioration despite adequate inotropic support.
    Journal of Paediatrics and Child Health 05/2013; · 1.25 Impact Factor
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    ABSTRACT: MAGE-C1/CT7, NY-ESO-1, GAGE and MAGE-A4 are members of the cancer/testis (CT) antigen family, which have been proposed as potential targets for cancer immunotherapy. To determine the prevalence and biologic relevance of the novel CT antigen MAGE-C1/CT7 and other antigens, 36 ovarian borderline tumours (BTs), 230 primary ovarian carcinomas (OCs) and 80 recurrent OCs were immunohistochemically analysed using the monoclonal antibodies CT7-33 (MAGE-C1/CT7), E978 (NY-ESO-1), clone 26 (GAGE) and 57B (MAGE-A4). Positivity of at least one CT antigen was present in 39.5 % (81/205) of primary OC and in 50 % (26/52) of all recurrences. Expression of the novel CT antigen MAGE-C1/CT7 was most commonly seen with positivity in 24.5 % of primary and 35.1 % of recurrent OC. MAGE-A4, GAGE and NY-ESO-1 expressions were seen in 22.7, 13.9 and 7.1 % of primary and 22.6, 17.5 and 8.9 % of recurrent OC, respectively. Analysis of histological subtypes (serous, endometrioid, clear cell, mucinous and transitional) exhibited variable expression with negativity in all mucinous OC. High-grade serous OC revealed CT antigen expression in 5.6 to 28 % with MAGE-C1/CT7 being the most frequent, but without correlation with stage or overall survival. MAGE-C1/CT7 expression and coexpression of CT antigens were significantly correlated with grade of endometrioid OC. None of the BT showed CT antigen expression. No significant correlation was seen with stage, overall survival or response to chemotherapy. In summary, CT antigens are expressed in a certain subset of OC with no expression in BT or OC of mucinous histology. These findings may have implications for the design of polyvalent vaccination strategies for ovarian carcinomas.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2013; · 2.68 Impact Factor
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    ABSTRACT: Seeking new biomarkers for epithelial ovarian cancer, the fifth most common cause of death from all cancers in women and the leading cause of death from gynaecological malignancies, we performed a meta-analysis of three independent studies and compared the results in regard to clinicopathological parameters. This analysis revealed that GAS6 was highly expressed in ovarian cancer and therefore was selected as our candidate of choice. GAS6 encodes a secreted protein involved in physiological processes including cell proliferation, chemotaxis, and cell survival. We performed immunohistochemistry on various ovarian cancer tissues and found that GAS6 expression was elevated in tumour tissue samples compared to healthy control samples (P < 0.0001). In addition, GAS6 expression was also higher in tumours from patients with residual disease compared to those without. Our data propose GAS6 as an independent predictor of poor survival, suggesting GAS6, both on the mRNA and on the protein level, as a potential biomarker for ovarian cancer. In clinical practice, the staining of a tumour biopsy for GAS6 may be useful to assess cancer prognosis and/or to monitor disease progression.
    BioMed Research International 01/2013; 2013:238284. · 2.71 Impact Factor
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    ABSTRACT: Due to impressive improvements in surgical repair options, even patients with complex congenital heart disease (CHD) may survive into adulthood and have a high risk of end-stage heart failure. Thus, the number of patients with CHD needing heart transplantation (HTx) has been increasing in the last decades. This paper summarizes the changing etiology of causes of death in heart failure in CHD. The main reasons, contraindications, and risks of heart transplantation in CHD are discussed and underlined with three case vignettes. Compared to HTx in acquired heart disease, HTx in CHD has an increased risk of perioperative death and rejection. However, outcome of HTx for complex CHD has improved over the past 20 years. Additionally, mechanical support options might decrease the waiting list mortality in the future. The number of patients needing heart-lung transplantation (especially for Eisenmenger's syndrome) has decreased in the last years. Lung transplantation with intracardiac repair of a cardiac defect is another possibility especially for patients with interatrial shunts. Overall, HTx will remain an important treatment option for CHD in the near future.
    Journal of Transplantation 01/2013; 2013:376027.
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    ABSTRACT: BACKGROUND: Pathologists are highly trained medical professionals who play an essential part in the diagnosis and therapy planning of malignancies and inflammatory diseases. Their work is associated with potential health hazards including injuries involving infectious human tissue, chemicals which are assumed to be carcinogenic or long periods of microscope and computer work. This study aimed to provide the first comprehensive assessment of the health situation of pathologists in Switzerland. METHODS: Pathologists in Switzerland were contacted via the Swiss Society of Pathologists and asked to answer an ethically approved, online anonymous questionnaire comprising 48 questions on occupational health problems, workplace characteristics and health behaviour. RESULTS: 163 pathologists participated in the study. Forty percent of pathologists reported musculoskeletal problems in the previous month. The overall prevalence was 76%. Almost 90% of pathologists had visual refraction errors, mainly myopia. 83% of pathologists had experienced occupational injuries, mostly cutting injuries, in their professional career; more than one fifth of participants reported cutting injuries in the last year. However, long lasting injuries and infectious diseases were rare. Depression and burnout affected every eighth pathologist. The prevalence of smoking was substantially below that of the general Swiss population. CONCLUSIONS: The results of this study suggest that more care should be taken in technical and personal protective measures, ergonomic workplace optimisation and reduction of work overload and work inefficiencies. Despite the described health risks, Swiss pathologists were optimistic about their future and their working situation. The high rate of ametropia and psychological problems warrants further study.
    BMC Public Health 12/2012; 12(1):1054. · 2.08 Impact Factor
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    ABSTRACT: About 15 years ago, the Swiss Society of Pathology has developed and implemented a board examination in anatomical pathology. We describe herein the contents covered by this 2-day exam (autopsy pathology, cytology, histopathology, molecular pathology, and basic knowledge about mechanisms of disease) and its exact modalities, sketch a brief history of the exam, and finish with a concise discussion about the possible objectives and putative benefits weighed against the hardship that it imposes on the candidates.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2012; 461(1):87-92. · 2.68 Impact Factor
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    ABSTRACT: Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.
    EMBO Molecular Medicine 06/2012; 4(8):808-24. · 7.80 Impact Factor
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    ABSTRACT: The G protein-coupled estrogen receptor (GPER) is thought to be involved in non-genomic estrogen responses as well as processes such as cell proliferation and migration. In this study, we analyzed GPER expression patterns from endometriosis samples and normal endometrial tissue samples and compared these expression profiles to those of the classical sex hormone receptors. A tissue microarray, which included 74 samples from different types of endometriosis (27 ovarian, 19 peritoneal and 28 deep-infiltrating) and 30 samples from normal endometrial tissue, was used to compare the expression levels of the GPER, estrogen receptor (ER)-alpha, ER-beta and progesterone receptor (PR). The immunoreactive score (IRS) was calculated separately for epithelium and stroma as the product of the staining intensity and the percentage of positive cells. The expression levels of the hormonal receptors were dichotomized into low (IRS < 6) and high (IRS > =6) expression groups. The mean epithelial IRS (+/-standard deviation, range) of cytoplasmic GPER expression was 1.2 (+/-1.7, 0-4) in normal endometrium and 5.1 (+/-3.5, 0-12) in endometriosis (p < 0.001), of nuclear GPER 6.4 (+/-2.6, 0-12) and 6.8 (+/-2.9, 2-12; p = 0.71), of ER-alpha 10.6 (+/-2.4, 3-12) and 9.8 (+/-3.0, 2-12; p = 0.26), of ER-beta 2.4 (+/-2.2; 0-8) and 5.6 (+/-2.6; 0-10; p < 0.001), and of PR 11.5 (+/-1.7; 3-12) and 8.1 (+/-4.5; 0-12; p < 0.001), respectively. The mean stromal IRS of nuclear GPER expression was 7.7 (+/-3.0; 2-12) in endometrium and 10.8 (+/-1.7; 6-12) in endometriosis (p < 0.001), of ER-alpha 8.7 (+/-3.1; 2-12) and 10.6 (+/-2.4; 2-12; p = 0.001), of ER-beta 1.8 (+/-2.0; 0-8) and 5.4 (+/-2.5; 0-10; p < 0.001), and of PR 11.7 (+/-0.9; 8-12) and 10.9 (+/-2.0; 3-12; p = 0.044), respectively. Cytoplasmic GPER expression was not detectable in the stroma of endometrium and endometriosis. The observed frequency of high epithelial cytoplasmic GPER expression levels was 50% (n = 30/60) in the endometriosis and none (0/30) in the normal endometrium samples (p < 0.001). High epithelial cytoplasmic GPER expression levels were more frequent in endometriomas (14/20, 70%; p = 0.01), as compared to peritoneal (9/18, 50%) or deep-infiltrating endometriotic lesions (7/22, 31.8%). The frequency of high stromal nuclear GPER expression levels was 100% (n = 74/74) in endometriosis and 76.7% (n = 23/30) in normal endometrium (p < 0.001). The frequency of high epithelial nuclear GPER expression levels did not differ between endometriosis and normal endometrium. The present data indicate a unique GPER expression pattern in endometriosis, especially in endometriomas as compared to the normal endometrium. The overexpression of GPER in endometriotic lesions suggests a potential role for GPER in the hormonal regulation of endometriosis, which should be taken into consideration for future hormonal treatment strategies.
    Reproductive Biology and Endocrinology 04/2012; 10:30. · 2.41 Impact Factor
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    ABSTRACT: Mutations of the tumor-suppressor gene ARID1A result in the loss of protein expression of the BRG-associated factor 250a (BAF250a), a large subunit of transcription-regulating Human SWI/SNF complexes, which have an important role in the control of cell proliferation and tumor suppression. ARID1A mutations are particularly frequent in endometriosis-associated ovarian clear cell and endometrioid carcinomas, and were recently described as a possible key mechanism and early step in the transformation of endometriosis into cancer. Here, we examined the immunohistochemical expression pattern of BAF250a in a tissue microarray including 74 endometriosis and 30 endometrium samples. Ovarian cancer samples (n=136) served as a control. Epithelial BAF250a expression was assessable in 90/104 (87%) and stromal BAF250a expression in 95/104 (91%) of the endometriosis, and endometrium cases due to lack of adequate tissue in some spots. Complete lack of BAF250a expression was observed in three endometriomas (n=3/20, 15%) and one deep-infiltrating endometriosis sample (n=1/22, 5%), but in none of the peritoneal endometriosis (n=0/16) and eutopic endometrium samples (n=0/30). A comparison of the mean immunoreactivity scores revealed a significantly lower expression rate of BAF250a in endometriomas compared with normal endometrium (P<0.0005), as well as peritoneal (P=0.003) and deep-infiltrating endometriosis (P=0.02). Our data demonstrates that a complete loss of BAF250a expression is observable in some endometriotic lesions, especially in endometriomas. In addition, we report that a partial loss of BAF250a expression is occurring in the form of cell clusters indicating a clonal loss of BAF250a expression in these cells. The loss of expression of the tumor-suppressor protein BAF250a in some endometriomas possibly indicates a risk of malignant transformation in these cases, which could be of importance in the determination of individual treatment strategies. However, its role and value as a prognostic parameter in endometriosis needs to be further studied.
    Modern Pathology 02/2012; 25(6):885-92. · 5.25 Impact Factor
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    ABSTRACT: Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets.
    PLoS ONE 01/2012; 7(2):e31885. · 3.53 Impact Factor
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    ABSTRACT: Infants with severe primary combined immunodeficiency (SCID) and children post-allogeneic hematopoietic stem cell transplantation (HSCT) are extremely susceptible to unusual infections. The lack of generic tools to detect disease-causing viruses among more than 200 potential human viral pathogens represents a major challenge to clinicians and virologists. We investigated retrospectively the causes of a fatal disseminated viral infection with meningoencephalitis in an infant with gamma C-SCID and of chronic gastroenteritis in 2 other infants admitted for HSCT during the same time period. Analysis was undertaken by combining cell culture, electron microscopy and sequence-independent single primer amplification (SISPA) techniques. Caco-2 cells inoculated with fecal samples developed a cytopathic effect and non-enveloped viral particles in infected cells were detected by electron microscopy. SISPA led to the identification of astrovirus as the pathogen. Both sequencing of the capsid gene and the pattern of infection suggested nosocomial transmission from a chronically excreting index case to 2 other patients leading to fatal infection in 1 and to transient disease in the others. Virus-specific, real-time reverse transcription polymerase chain reaction was then performed on different stored samples to assess the extent of infection. Infection was associated with viremia in 2 cases and contributed to death in 1. At autopsy, viral RNA was detected in the brain and different other organs, while immunochemistry confirmed infection of gastrointestinal tissues. This report illustrates the usefulness of the combined use of classical virology procedures and modern molecular tools for the diagnosis of unexpected infections. It illustrates that astrovirus has the potential to cause severe disseminated lethal infection in highly immunocompromised pediatric patients.
    PLoS ONE 11/2011; 6(11):e27483. · 3.53 Impact Factor
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    ABSTRACT: Alpha-methylacyl-CoA racemase (AMACR) is involved in the cellular metabolism of fatty acids. It is a prognostic factor in prostate and colorectal cancer. So far, little is known about its expression and prognostic role in ovarian cancer. We investigated the expression of AMACR in a total of 420 ovarian tumors (388 carcinomas, 32 borderline tumors) by immunohistochemistry on tissue microarrays of two independent patient cohorts. In both cohorts, cytoplasmic AMACR expression was identified in 11.8% (16/136) and 5.4% (13/239), respectively, of the ovarian carcinomas. In contrast, borderline tumors did not show any AMACR expression. AMACR expression was significantly associated with histological subtype, FIGO stage, and grade in one cohort and low estrogen receptor levels in the other cohort. In univariate analysis, AMACR expression was significantly associated with poor overall survival (log rank, p = 0.006) and an independent prognostic factor in a multivariate analysis (HR 3.3; CI 1.3-7.9; p = 0.008) but could not be verified in the second cohort. Unlike in other tumor entities, AMACR expression does not seem to have an unequivocal prognostic impact in ovarian cancer. The prevalence may limit the value of AMACR for the differential diagnosis between metastatic colorectal carcinomas and primary ovarian carcinomas, whereas the association with estrogen receptor expression deserves further studies.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2011; 459(1):91-7. · 2.68 Impact Factor
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    ABSTRACT: About 70% of epithelial ovarian cancer patients (EOC) are diagnosed at advanced stage with a five-year survival rate of only 30%. Whilst CA125 detects peritoneally-spread disease, it has limited sensitivity for early cancers, many of which are potentially curable. We compared the new commercially available tumor marker HE4 with CA125 individually, in combination, within the risk of malignancy index (RMI) and the newly defined risk of malignancy algorithm (ROMA). Our prospectively-collected cohort of 160 patients consisted of healthy controls, benign diseases, and borderline tumors/adenocarcinomas of ovarian, tubal, peritoneal and endometrial origin. HE4 and CA125 were measured in serum using standardized ELISA. Both markers showed similar diagnostic performance in the detection of EOC at clinically defined thresholds (CA125 35U/ml; HE4 70pM) but HE4 was not elevated in endometriosis. Comparison of non-malignant diagnoses (n=71) versus early stage ovarian and tubal cancers (n=19) revealed that HE4 and ROMA displayed the best diagnostic performance (AUC 0.86/0.87, specificity 85.9%/87.3% and sensitivity 78.9%/78.9%, respectively). Whilst RMICA125 detects peritoneal cancer better than all other models (AUC 0.99, specificity 97.2%, sensitivity 80.0%), there is no other detection benefit from RMI compared to HE4 alone or included in ROMA. The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.
    Gynecologic Oncology 03/2011; 121(3):487-91. · 3.93 Impact Factor
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    ABSTRACT: Abrogation of negative feedback control represents a fundamental requirement for aberrantly activated signaling pathways to promote malignant transformation and resistance to therapy. Here we identify URI, which encodes a mitochondrial inhibitor of PP1γ and PP1γ-mediated feedback inhibition of S6K1-BAD survival signaling, as an oncogene amplified and overexpressed in ovarian cancer cell lines and human ovarian carcinomas. URI is an "addicting" oncogene selectively required for the survival of ovarian cancer cells with increased URI copy number. By constitutively detaining PP1γ in inactive complexes, URI sustains S6K1 survival signaling under growth factor-limiting conditions and mediates resistance of cells to cisplatin. Thus, oncogenic activation of URI defines an important mechanism for activating mitochondrial S6K1-BAD signaling and promoting cell survival through disabling PP1γ-dependent negative feedback inhibition.
    Cancer cell 03/2011; 19(3):317-32. · 25.29 Impact Factor
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    ABSTRACT: Epigenetic regulation is an important mechanism leading to cancer initiation and promotion. Histone acetylation by histone deacetylases (HDACs) represents an important part of it. The development of HDAC inhibitors has identified the utility of HDACs as a therapeutic target. Little is known about the epigenetic regulation of vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell cancer (VSCC). In this study, the expression of class I HDACs (HDAC 1, 2 and 3) was compared in a series of VIN and VSCC tissues. A tissue micro array (TMA) with specimens from 106 patients with high-grade VIN and 59 patients with vulvar cancer was constructed. The expression of HDACs 1, 2 and 3 were analyzed with immunohistochemistry (IHC). The nuclear expression pattern was evaluated in terms of intensity and percentage of stained nuclei and was compared between vulvar preinvasive lesions and vulvar cancer. HDAC 2 expression was significantly higher in VIN than in VSCC (p < 0.001, Fisher's test). Also, 88.7% (n = 94/106) of VIN samples and only 54.5% (n = 31/57) of VSCC samples were scored at the maximum level. Conversely, HDAC 3 expression was significantly higher in VSCC (93%, 53/57) compared to VIN (73.6%, 78/106, p = 0.003), whereas only a small difference in the expression of HDAC 1 was found between these two entities of vulvar neoplasia. These results suggest that epigenetic regulation plays a considerable role in the transformation of VIN to invasive vulvar neoplasia.
    BMC Cancer 01/2011; 11:463. · 3.33 Impact Factor
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    ABSTRACT: While mammary Paget's disease (MPD) is clearly linked to breast cancer, the histogenesis of extramammary Paget's disease (EMPD) is controversial. Recently NY-BR-1, a differentiation antigen expressed in the breast and in skin adnexal structures was identified. Its protein expression is restricted to normal and neoplastic breast epithelium and to adnexal tumors of the skin. In this study, we examine NY-BR-1 expression by immunohistochemistry in 24 MPD cases with synchronous ductal carcinoma in situ or invasive breast cancer. Results were compared with 26 cases of EMPD of men (n= 4) and women (n= 22) as well as in apoeccrine glands of the axilla and mammary-like glands of the anogenital region. We found NY-BR-1 positivity in 18 of 24 MPD (75%) and in 21 of 26 EMPD (80.8%). All apoeccrine glands of the axilla and mammary-like glands of the anogenital region were NY-BR-1-positive. NY-BR-1 expression is a common finding in MPD and in EMPD. When considering the diagnosis of Paget's disease, NY-BR-1 is a useful diagnostic marker. Furthermore NY-BR-1 positivity in apoeccrine glands of the axilla and anogenital region suggests a potential histogenetic link between these structures and Paget's disease.
    Pathology International 11/2010; 60(11):726-34. · 1.72 Impact Factor
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    ABSTRACT: Recommendations for intraoperative and postoperative breast sentinel lymph node (SLN) processing differ widely. Micrometastases and isolated tumor cells (ITC) have recently been proposed as prognostically and therapeutically relevant. We compared 3 SLN protocols with regard to intraoperative and postoperative diagnosis. SLN in cohort I (270 patients) were intraoperatively assessed by stereomicroscopy. Intraoperative frozen section (IFS) was used only in stereomicroscopically suspicious SLN. In cohort II (197 patients), all SLN were examined with only 1 IFS. Final SLN workup in cohorts I and II consisted of complete step sectioning with immunohistochemistry. In cohort III (268 patients) 2 or more IFS were performed followed by 3 step sections and immunohistochemistry. pN1 stages were significantly higher in cohorts I and II (33.3% and 34.0% respectively) than in cohort III (24.6%). Intraoperative false negativity for the detection of metastases (pN1) ranged from 54.4% (cohort I) and 35.8% (cohort II) to 21.2% (cohort III). In contrast, ITC were detected significantly more frequently in cohort I (9.3%) and cohort II (14.7%) than in cohort III (1.9%). Higher rates of SLN metastases and ITC in cohort I/II compared to cohort III suggest that IFS may result in tissue loss thus increasing the risk of missing metastases. Sparse IFS but complete postoperative SLN workup with step sectioning and immunohistochemistry provides more accurate information regarding minimal disease in SLN, but often results in delayed axillary lymph node dissection. This is important for preoperative patient information and recommendations in SLN processing protocols.
    Annals of Surgical Oncology 05/2010; 17(11):2892-8. · 4.12 Impact Factor

Publication Stats

479 Citations
184.18 Total Impact Points

Institutions

  • 1998–2014
    • University of Zurich
      • Institut für Diagnostische und interventionelle Radiologie
      Zürich, Zurich, Switzerland
  • 2007
    • Pathologie Institut Enge
      Zürich, Zurich, Switzerland
  • 2002
    • ETH Zurich
      • Institute of Biochemistry
      Zürich, ZH, Switzerland