Elvira Stacher

Medical University of Graz

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Andrea Olschewski

Medical University of Graz

Helmut Popper

Medical University of Graz

Horst Olschewski

Medical University of Graz

Katharina Leithner

Medical University of Graz

Andelko Hrzenjak

Ludwig Boltzmann Institute for Lung Vascular Research

Iris Halbwedl

Medical University of Graz

Christoph Wohlkoenig

Medical University of Graz

Zoltán Bálint

Babeș-Bolyai University

Chandran Nagaraj

Ludwig Boltzmann Institute for Lung Vascular Research

Grażyna Kwapiszewska

Medical University of Graz

Cooperative Institutions

Medical University of Graz

121

University of Graz

Medical University of Vienna

Ludwig Boltzmann Institute for Lung Vascular Research

University of Giessen

BioTechMed-Graz

German Center for Lung Research

Graz University Hospital

University of Colorado Denver

University of Colorado Anschutz Medical Campus

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A 55-year-old craftsman with dyspnea and clubbing: a case report

Cases Journal (2009)

Stefan Scheidl Gábor Kovács Elvira Stacher Helmut Popper Horst Olschewski

Clubbing is very uncommon in respiratory bronchiolitis-associated interstitial lung disease, and primarily raises the suspicion of idiopathic pulmonary fibrosis in a patient presenting with diffuse parenchymal lung disease. If idiopathic pulmonary fibrosis can be excluded, clubbing should raise the suspicion of an occult tumour.We describe a heavy smoker presenting with dyspnea and severe clubbing. Surgical lung biopsy revealed the histologic diagnosis of respiratory bronchiolitis-associated interstitial lung disease. Respiratory bronchiolitis-associated interstitial lung disease is a distinct clinicopathologic entity within idiopathic interstitial pneumonia patients described almost exclusively in cigarette smokers. The disease is associated with a good prognosis and mild symptoms but not with clubbing. After smoking cessation the radiologic findings of interstitial lung disease improved in parallel with improvement in lung function and gas exchange. However, a central squamous cell carcinoma was detected in the follow-up.In this case, clubbing was most probably caused by the occult tumor rather than by respiratory bronchiolitis-associated interstitial lung disease.

Usual interstitial pneumonia

Lung biopsy

Idiopathic interstitial pneumonia

10.4076/1757-1626-2-8579

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Citations (4)

Pulmonary histiocytic sarcoma mimicking pulmonary Langerhans cell histiocytosis in a young adult presenting with spontaneous pneumothorax: a potential diagnostic pitfall

Virchows Archiv (2009)

Elvira Stacher Christine Beham‐Schmid Hans‐Joachim Terpe Nektaria Simiantonaki Helmut Popper

Histiocytic sarcoma

Eosinophilic granuloma

Langerhans Cell Histiocytosis

CD68

10.1007/s00428-009-0801-3

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Citations (17)

Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy

Lung Cancer (2008)

Katharina Leithner Elvira Stacher Robert Wurm Ferdinand Ploner Franz Quehenberger

10.1016/j.lungcan.2008.10.015

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Citations (31)

Chromosomal aberrations as detected by array comparative genomic hybridization in early low-grade intraepithelial neoplasias of the breast

Histopathology (2011)

Elvira Stacher Vivien Boldt Sebastian Leibl Iris Halbwedl Helmut Popper

Low-grade flat ductal intraepithelial neoplasia (DIN1a, flat epithelial atypia) is one of the earliest morphologically recognizable neoplastic lesions of the breast. Frequently, it occurs concomitantly with lobular intraepithelial neoplasia (LIN). We aimed to elucidate chromosomal aberrations in these early neoplastic breast lesions with the use of array comparative genomic hybridization analysis.Laser capture microdissection of 12 archival formalin-fixed, paraffin-embedded specimens harbouring foci of both DIN1a and LIN was performed. All analysed cases of DIN1a and LIN showed chromosomal gains and losses. The aberration encountered most often was loss of 16q, noted in seven DIN1a (70% of those successfully examined) and 10 LIN (91%) cases. The next most common alteration was a gain on 1q, noted in four DIN1a (40%) and seven LIN (64%) cases.The results show concurrent chromosomal aberrations of 1q gains and 16q losses in several cases with coexisting LIN and DIN1a. These aberrations are known to be common in low-grade invasive (ductal and lobular) carcinomas as well as in more advanced (conventional) types of low-grade ductal intraepithelial neoplasia (DIN) (low-grade ductal carcinoma in situ). Our results raise the possibility of similar molecular-genetic pathways in coexisting LIN and low-grade flat DIN.

Comparative genomic hybridization

Microdissection

Laser capture microdissection

Lobular carcinoma

Atypia

Nuclear atypia

Invasive lobular carcinoma

Carcinoma in situ

10.1111/j.1365-2559.2011.03918.x

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Citations (15)

Androgen receptor expression in breast cancer patients tested for BRCA1 and BRCA2 mutations

Histopathology (2010)

Gunda Pristauz Edgar Petru Elvira Stacher Jochen B. Geigl Thomas Schwarzbraun

To assess the expression of receptors for androgen (AR), oestrogen (ER) and progesterone (PR) as well as human epidermal growth factor receptor type 2 (Her-2/neu) status of breast carcinomas in breast cancer susceptibility gene (BRCA) BRCA1/2 mutation carriers and BRCA1/2 negative tested women.One hundred and thirty-five breast cancers in women tested for BRCA1/2 mutations. Screening for BRCA1 and BRCA2 mutations was performed by direct sequencing of all BRCA1 and BRCA2 exons as well as the surrounding intronic sequences. Additionally, BRCA genes were analysed with multiplex ligation-dependent probe amplification. Consecutive paraffin sections were examined immunohistochemically for AR, ER, PR and Her-2/neu.Of the 135 tumours, 43 (32%) were BRCA1-related, 18 (13%) were BRCA2-related and 74 (55%) were BRCA1/2-negative. Seventy-two per cent of the BRCA1-related, 22% of the BRCA2-related and 12% of the BRCA1/2-negative tumours were triple (ER, PR, Her2neu)-negative. Eighty-four per cent of BRCA1 mutated cancers were high-grade (G3) tumours. ARs were expressed in 30% (13 of 43) of BRCA1-related, in 78% (14 of 18) in BRCA2-related tumours and in 76% (56 of 74) in BRCA1/2 negative tumours. Twenty-one per cent of ER-negative BRCA1-related tumours expressed androgen receptors.Approximately one in five BRCA1 mutated breast cancers negative for ER and PR express androgen receptors. Modulation of AR might open a new avenue for treating these high-risk cancers.

Progesterone receptor

10.1111/j.1365-2559.2010.03724.x

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Citations (31)

Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease

AJP Lung Cellular and Molecular Physiology (2013)

James M. Hunt Brian Bethea Xiang Liu Aneta Gandjeva Pradeep P.A. Mammen

Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries.

10.1152/ajplung.00186.2013

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Citations (50)

576 Expression of TASK-1 and TASK-3 channels in non-small cell lung cancer

European Journal of Cancer Supplements (2010)

Katharina Leithner Christoph Wohlkoenig Y. Li Binwu Tang Chinmayee B. Nagaraj

Expression (computer science)

10.1016/s1359-6349(10)71377-x

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Citations (0)

Primary patient-derived lung adenocarcinoma cell culture challenges the association of cancer stem cells with epithelial-to-mesenchymal transition

Scientific Reports (2017)

Verena Tiran Joerg Lindenmann Luka Brčić Ellen Heitzer Stefanie Stanzer

The cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) models have been closely associated and used to describe both the formation of metastasis and therapy resistance. We established a primary lung cell culture from a patient in a clinically rare and unique situation of primary resistant disease. This culture consisted of two biologically profoundly distinct adenocarcinoma cell subpopulations, which differed phenotypically and genotypically. One subpopulation initiated and sustained in spheroid cell culture (LT22s) whereas the other subpopulation was only capable of growth and proliferation under adherent conditions (LT22a). In contrast to our expectations, LT22s were strongly associated with the epithelial phenotype, and expressed additionally CSC markers ALDH1 and CD133, whereas the LT22a was characterized as mesenchymal with lack of CSC markers. The LT22s cells also demonstrated an invasive behavior and mimicked gland formation. Finally, LT22s were more resistant to Cisplatin than LT22a cells. We demonstrate a primary lung adenocarcinoma cell culture derived from a patient with resistant disease, with epithelial aggressive subpopulation of cells associated with stem cell features and therapy resistance. Our findings challenge the current model associating CSC and disease resistance mainly to mesenchymal cells and may have important clinical implications.

10.1038/s41598-017-09929-0

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Citations (32)

Abstract 15009: Increased Expression of TMEM16A May Lead to Depolarization of Human Pulmonary Arterial Smooth Muscle Cells in IPAH

Rita Papp Chandran Nagaraj Zoltán Bálint Bence Nagy Elvira Stacher

Introduction: Depolarization of pulmonary arterial smooth muscle cells (PASMCs) and subsequent increase of intracellular calcium concentration are suggested to be crucial events in the pathomechanism of pulmonary hypertension. In animal models of PH the calcium activated chloride channel TMEM16A has been recently identified as a novel ion channel contributing to sustained pulmonary vasoconstriction. Hypothesis: We hypothetised that TMEM16A is also upregulated in human pulmonary arteries obtained from patients with idiopathic pulmonary arterial hypertension (IPAH) and it is responsible for a relevant depolarizing current. Methods: Laser capture microdissection (LCM) of the intima and media layers of pulmonary arteries from healthy donors (n=7) and IPAH patients (n=7) was performed in order to investigate the expression of several chloride channels by QPCR. These findings were confirmed on cultured PASMCs isolated from healthy donor and IPAH lungs. The membrane potential of PASMCs from both groups was measured with the patch-clamp technique and the effect of the specific TMEM16A inhibitor T16A-inh01 (10 μM) was studied. Results: Our QPCR studies have shown marked upregulation of TMEM16A both in the LCM material and in the PASMCs isolated from IPAH patients. Measurement of the resting membrane potential showed that the PASMCs from IPAH patients were more depolarized compared to the PASMCs of healthy donors (-34 ± 2 mV vs -47 ± 2 mV, p< 0.05). Interestingly, treatment of the IPAH PASMCs with T16A-inh01 resulted in a significant hyperpolarization of the membrane potential (-41 ± 2 mV, p< 0.05 compared to untreated IPAH). Conclusions: Our data suggest that TMEM16A is upregulated in the PASMCs of human IPAH patients and the resulting increase in chloride efflux indeed contributes to PASMC depolarization, which may lead to excess vasoconstriction and remodeling of pulmonary arteries.

Hypoxic pulmonary vasoconstriction

Calcium in biology

Hyperpolarization

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Toward an Improved Definition of the Tumor Spectrum Associated With BAP1 Germline Mutations

Journal of Clinical Oncology (2012)

Thomas Wiesner Isabella Fried Peter Ulz Elvira Stacher Helmut Popper

BAP1

10.1200/jco.2011.41.2965

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Citations (95)