Publications by authors named "Sabine Zöchbauer-Müller"

61 Publications

Lung Cancer in Austria.

J Thorac Oncol 2021 May;16(5):725-733

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1016/j.jtho.2020.10.158DOI Listing
May 2021

Neutrophil-to-Lymphocyte Ratio is superior to other leucocyte-based ratios as a prognostic predictor in radiosurgically treated non-small cell lung cancer brain metastases patients under immunotherapy or targeted therapy.

World Neurosurg 2021 Apr 17. Epub 2021 Apr 17.

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: The predictive value of pre-radiosurgery leucocyte-based prognostic ratios was investigated in a selected cohort of non-small cell lung cancer patients (NSCLC) patients with radiosurgically treated brain metastases (BM) and concomitant immunotherapy (IT) or targeted therapy (TT).

Methods: We performed a retrospective analysis of 166 NSCLC BM patients treated with Gamma Knife Radiosurgery. The Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Lymphocyte-to-Monocyte Ratio (LMR) were assessed within 14 days prior to radiosurgical treatment.

Results: In radiosurgically treated NSCLC BM patients with concomitant IT or TT, the estimated median survival after GKRS1 was significantly longer in patients with a NLR cut-off value <5 (p=0.038). Consequently, the Cox regression model for NLR cut-off value groups revealed a significant hazard ratio (HR) of 1.519 (95%CI=1.020-2.265; p=0.040). In addition, each increase in the NLR of 1 equaled an increase of 5.4% in risk of death (HR 1.054; 95%CI=1.024-1.085; p<0.001). After adjusting for sex, age, Karnofsky Performance Status Scale, and presence of extracranial metastases, the NLR remained a significant and independent predictor for survival (HR 1.047; 95%CI=1.017-1.078; p=0.002). In contrast, PLR and LMR did not exhibit the same predictive value among our selected cohort of radiosurgically treated BM patients with IT or TT.

Conclusion: In NSCLC BM patients, treated with IT or TT, pre-radiosurgical NLR represents a simple prognostic predictor for survival and is superior to other leucocyte-based ratios. Thus, especially NLR may be relevant for clinical decision making, therapeutic evaluation, patient counselling, and appropriate stratification of future clinical trials among radiosurgically treated BM patients.
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http://dx.doi.org/10.1016/j.wneu.2021.04.033DOI Listing
April 2021

Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare Exon 20 Mutation.

Front Oncol 2020 26;10:593852. Epub 2021 Jan 26.

Comprehensive Cancer Center, Vienna, Austria.

Unlike most other primary epidermal growth factor receptor () mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all mutations, are generally considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However, exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain exon 20 insertions, these findings warrant further investigation.
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http://dx.doi.org/10.3389/fonc.2020.593852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871906PMC
January 2021

Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy.

Cancers (Basel) 2020 Dec 7;12(12). Epub 2020 Dec 7.

Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria.

The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3-11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT ( < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.
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http://dx.doi.org/10.3390/cancers12123668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762317PMC
December 2020

Pre-radiosurgery leucocyte ratios and modified glasgow prognostic score predict survival in non-small cell lung cancer brain metastases patients.

J Neurooncol 2021 Jan 11;151(2):257-265. Epub 2020 Nov 11.

Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Introduction: The predictive value of the pre-radiosurgery Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR) and the modified Glasgow Prognostic Score (mGPS) was assessed for the first time in a homogenous group of NSCLC brain metastaes (BM) patients.

Methods: We retrospectively evaluated 185 NSCLC-BM patients, who were treated with Gamma Knife Radiosurgery (GKRS). Patients with immunotherapy or targeted therapy were excluded. Routine laboratory parameters were reviewed within 14 days before GKRS1.

Results: Median survival after GKRS1 was significantly longer in patients with NLR < 5 (p < 0.001), PLR < 180 (p = 0.003) and LMR ≥ 4 (p = 0.023). The Cox regression model for the continuous metric values revealed that each increase in the NLR of 1 equaled an increase of 4.3% in risk of death (HR: 1.043; 95%CI = 1.020-1.067, p < 0.001); each increase in the PLR of 10 caused an increase of 1.3% in risk of death (HR: 1.013; 95%CI = 1.004-1.021; p = 0.003) and each increase in the LMR of 1 equaled a decrease of 20.5% in risk of death (HR: 0.795; 95%CI = 0.697-0.907; p = 0.001). Moreover, the mGPS group was a highly significant predictor for survival after GKRS1 (p < 0.001) with a HR of 2.501 (95%CI = 1.582-3.954; p < 0.001). NLR, PLR, LMR values and mGPS groups were validated as independent prognostic factors for risk of death after adjusting for sex, KPS, age and presence of extracranial metastases.

Conclusion: NLR, PLR, LMR and mGPS represent effective and simple tools to predict survival in NSCLC patients prior to radiosurgery for brain metastases.
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http://dx.doi.org/10.1007/s11060-020-03660-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875838PMC
January 2021

Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy.

Blood 2021 Mar;137(12):1669-1678

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, and.

The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.
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http://dx.doi.org/10.1182/blood.2020007878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016631PMC
March 2021

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field.

ESMO Open 2020 10;5(5):e000880

Division of Oncology, Department for Medicine I, Medical University of Vienna, Wien, Austria.

Background: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology.

Methods: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system.

Results: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported.

Conclusions: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.
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http://dx.doi.org/10.1136/esmoopen-2020-000880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555099PMC
October 2020

Homeopathic Treatment as an Add-On Therapy May Improve Quality of Life and Prolong Survival in Patients with Non-Small Cell Lung Cancer: A Prospective, Randomized, Placebo-Controlled, Double-Blind, Three-Arm, Multicenter Study.

Oncologist 2020 12 7;25(12):e1930-e1955. Epub 2020 Nov 7.

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for Lung Health, Otto Wagner Hospital and Sigmund Freud University, Medical School, Vienna, Austria.

Lessons Learned: Conventional medicine and homeopathy work well together. Quality of life improves with additive homeopathy in patients with non-small cell lung cancer (NSCLC). Survival improves with additive homeopathy in patients with NSCLC.

Background: Patients with advanced non-small cell lung cancer (NSCLC) have limited treatment options. Alongside conventional anticancer treatment, additive homeopathy might help to alleviate side effects of conventional therapy. The aim of the present study was to investigate whether additive homeopathy might influence quality of life (QoL) and survival in patients with NSCLC.

Methods: In this prospective, randomized, placebo-controlled, double-blind, three-arm, multicenter, phase III study, we evaluated the possible effects of additive homeopathic treatment compared with placebo in patients with stage IV NSCLC, with respect to QoL in the two randomized groups and survival time in all three groups. Treated patients visited the outpatients' centers every 9 weeks: 150 patients with stage IV NSCLC were included in the study; 98 received either individualized homeopathic remedies (n = 51) or placebo (n = 47) in a double-blinded fashion; and 52 control patients without any homeopathic treatment were observed for survival only. The constituents of the different homeopathic remedies were mainly of plant, mineral, or animal origin. The remedies were manufactured by stepwise dilution and succussion, thereby preparing stable Good Manufacturing Practice grade formulations.

Results: QoL as well as functional and symptom scales showed significant improvement in the homeopathy group when compared with placebo after 9 and 18 weeks of homeopathic treatment (p < .001). Median survival time was significantly longer in the homeopathy group (435 days) versus placebo (257 days; p = .010) as well as versus control (228 days; p < .001). Survival rate in the homeopathy group differed significantly from placebo (p = .020) and from control (p < .001).

Conclusion: QoL improved significantly in the homeopathy group compared with placebo. In addition, survival was significantly longer in the homeopathy group versus placebo and control. A higher QoL might have contributed to the prolonged survival. The study suggests that homeopathy positively influences not only QoL but also survival. Further studies including other tumor entities are warranted.
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http://dx.doi.org/10.1002/onco.13548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108047PMC
December 2020

Non-interventional LUME-BioNIS study of nintedanib plus docetaxel after chemotherapy in adenocarcinoma non-small cell lung cancer: A subgroup analysis in patients with prior immunotherapy.

Lung Cancer 2020 10 8;148:159-165. Epub 2020 Aug 8.

Department of Pathology, Aberdeen Royal Infirmary, Foresterhill Rd, Aberdeen AB25 2ZN, United Kingdom. Electronic address:

Objectives: To evaluate the effectiveness and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) previously treated with both chemo- and immunotherapy.

Materials And Methods: LUME-BioNIS is a European, prospective, multicenter, non-interventional study of patients with advanced adenocarcinoma NSCLC, who initiated nintedanib plus docetaxel after first-line chemotherapy in routine practice according to the approved nintedanib EU label. The primary objective is to explore whether molecular biomarkers can predict overall survival (OS). Information on clinical or radiologic progression and death, and adverse drug reactions (ADRs)/fatal adverse events (AEs) was collected during follow-up. Here, we report a subgroup analysis evaluating outcomes in immunotherapy-pretreated patients.

Results: Of 260 enrolled patients, 67 (25.8%) had prior immunotherapy and were included in this subgroup analysis. Prior immunotherapy was administered in first-line in 20 patients (29.9%; combined with chemotherapy in 4 patients [6.0%]) and later-lines in 47 patients (70.1%), and most commonly comprised nivolumab (39 patients; 58.2%), atezolizumab (14 patients; 20.9%) and pembrolizumab (11 patients; 16.4%). Nintedanib plus docetaxel was given in second-line in 10 patients (14.9%) and in later-lines in 57 patients (85.1%). Median OS was 8.8 months (95% confidence interval [CI]: 7.0-11.5) and median progression-free survival (PFS) was 4.6 months (95% CI: 3.5-5.7). Among 55 patients with available data, rates of objective response and disease control were 18.2% and 78.2%, respectively. In 65 patients evaluable for safety, the most common on-treatment ADRs/AEs were malignant neoplasm progression (19 patients; 29.2%), diarrhea (21 patients; 32.3%) and nausea (10 patients; 15.4%).

Conclusions: Used according to the approved nintedanib label in routine practice, nintedanib plus docetaxel demonstrated clinical effectiveness, with no unexpected safety findings, in patients with prior chemotherapy and first- or later-line immunotherapy. These data add to the real-world evidence that can inform clinical decisions in the changing therapeutic landscape.
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http://dx.doi.org/10.1016/j.lungcan.2020.08.004DOI Listing
October 2020

Neurological symptom burden impacts survival prognosis in patients with newly diagnosed non-small cell lung cancer brain metastases.

Cancer 2020 10 17;126(19):4341-4352. Epub 2020 Jul 17.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Brain metastases (BM) are a frequent complication of advanced cancer and are characterized by a variety of neurological symptoms. Although the presence of neurological symptoms is included in the response assessment in patients with primary brain tumors, to the authors' knowledge little is known regarding the prognostic impact of neurological symptoms in patients with BM.

Methods: Patients with newly diagnosed BM from non-small cell lung cancer were identified from the Vienna Brain Metastasis Registry and were evaluated according to the incidence, distribution, and prognostic impact of neurological symptoms at the time of diagnosis of BM.

Results: A total of 1608 patients (57.3% male and 42.7% female; median age, 62 years) were available for further analyses. Neurological symptoms including focal deficits (985 patients; 61.3%), signs of increased intracranial pressure (483 patients; 30.0%), epileptic seizures (224 patients; 13.9%), and neuropsychological symptoms (233 patients; 14.5%) were documented in 1186 of the 1608 patients (73.8%). Patients with asymptomatic BM presented with a longer median overall survival after the diagnosis of BM compared with patients with symptomatic BM (11 months vs 7 months; P < .001). In multivariate analysis with a diagnosis-specific graded prognostic assessment (hazard ratio, 1.41; 95% CI, 1.33-1.50 [P < .001]), the presence of neurological symptoms (hazard ratio, 1.39; 95% CI, 1.23-1.57 [P < .001]) was found to be independently associated with survival prognosis from the time of diagnosis of BM.

Conclusions: Neurological symptoms at the time of BM diagnosis demonstrated a strong and independent association with survival prognosis. The results of the current study have highlighted the need for the integration of the presence of neurological symptoms into the prognostic assessment of patients with BM from non-small cell lung cancer.

Lay Summary: Neurological symptom evaluation is included regularly in the assessment of patients with primary brain tumors. However, to the authors' knowledge, little is known regarding the prognostic impact in patients with newly diagnosed brain metastases (BM). The current study has provided a detailed clinical characterization of the incidence, distribution, and prognostic impact of neurological symptoms in a large, real-life cohort of patients with BM from non-small cell lung cancer. In this cohort, neurological symptoms at the time of diagnosis of BM demonstrated a strong, independent prognostic impact on the survival prognosis. The results of the current study have highlighted the need for the integration of neurological symptom burden into the prognostic assessment of patients with BM from non-small cell lung cancer.
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http://dx.doi.org/10.1002/cncr.33085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540353PMC
October 2020

Systemic Inflammation and Activation of Haemostasis Predict Poor Prognosis and Response to Chemotherapy in Patients with Advanced Lung Cancer.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, 1190 Vienna, Austria.

Systemic inflammation and activation of haemostasis are common in patients with lung cancer. Both conditions support tumour growth and metastasis. Therefore, inflammatory and haemostatic biomarkers might be useful for prediction of survival and therapy response. Patients with unresectable/metastatic lung cancer initiating 1st-line chemotherapy ( = 277, 83% non-small cell lung cancer) were followed in a prospective observational cohort study. A comprehensive panel of haemostatic biomarkers (D-dimer, prothrombin fragment 1+2, soluble P-selectin, fibrinogen, coagulation factor VIII, peak thrombin generation), blood count parameters (haemoglobin, leucocytes, thrombocytes) and inflammatory markers (neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, C-reactive protein) were measured at baseline. We assessed the association of biomarkers with mortality, progression-free-survival (PFS) and disease-control-rate (DCR). A biomarker-based prognostic model was derived. Selected inflammatory and haemostatic biomarkers were strong and independent predictors of mortality and therapy response. The strongest predictors (D-dimer, LMR, CRP) were incorporated in a unified biomarker-based prognostic model (1-year overall-survival (OS) by risk-quartiles: 79%, 69%, 51%, 24%; 2-year-OS: 53%, 36%, 23%, 8%; log-rank < 0.001). The biomarker-based model further predicted shorter PFS and lower DCR. In conclusion, inflammatory and haemostatic biomarkers predict poor prognosis and treatment-response in patients with advanced lung cancer. A biomarker-based prognostic score efficiently predicts mortality and disease progression beyond clinical characteristics.
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http://dx.doi.org/10.3390/cancers12061619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352812PMC
June 2020

Gender differences in molecular-guided therapy recommendations for metastatic malignant mesothelioma.

Thorac Cancer 2020 07 21;11(7):1979-1988. Epub 2020 May 21.

Division of Clinical Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile.

Methods: In this single-center, real-world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next-generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off-label therapy custom-tailored to the individual patient.

Results: In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD-L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender-specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease.

Conclusions: Our observations suggest that a molecular-guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials.
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http://dx.doi.org/10.1111/1759-7714.13491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327667PMC
July 2020

Prognostic assessment in patients with newly diagnosed small cell lung cancer brain metastases: results from a real-life cohort.

J Neurooncol 2019 Oct 27;145(1):85-95. Epub 2019 Aug 27.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Purposes: Brain metastases (BM) are a frequent complication in small cell lung cancer (SCLC), resulting in a reduced survival prognosis. Precise prognostic assessment is an important foundation for treatment decisions and clinical trial planning.

Methods: Patients with newly diagnosed SCLC BM were identified from the Vienna Brain Metastasis Registry and evaluated concerning prognostic factors.

Results: 489 patients (male 62.2%, female 37.8%; median age 61 years) were included. Neurological symptoms were present in 297/489 (60.7%) patients. A- to oligosymptomatic patients (5 vs. 9 months, p = 0.030) as well as patients with synchronous diagnosis of BM and primary tumor (5 vs. 9 months, p = 0.008) presented with improved overall survival (OS) prognosis. RPA (HR 1.66; 95% CI 1.44-1.91; p < 0.001), GPA (HR 1.65; p < 0.001), DS-GPA (HR 1.60; p < 0.001) and LabBM score (HR 1.69; p < 0.001) were statistically significantly associated with OS. In multivariate analysis, DS-GPA (HR 1.59; p < 0.001), neurological deficits (HR 1.26; p = 0.021) and LabBM score (HR 1.57; p < 0.001) presented with statistical independent association with OS.

Conclusion: A- to oligosymptomatic BM as well as synchronous diagnosis of SCLC and BM were associated with improved OS. Established prognostic scores could be validated in this large SCLC BM real-life cohort.
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http://dx.doi.org/10.1007/s11060-019-03269-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775039PMC
October 2019

SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness.

Sci Rep 2019 06 24;9(1):9139. Epub 2019 Jun 24.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to its genetic and molecular basis and to patients´ outcome. Clinical, cytogenetic, and mutational data are used to classify patients into risk groups with different survival, however, within-group heterogeneity is still an issue. Here, we used a robust likelihood-based survival modeling approach and publicly available gene expression data to identify a minimal number of genes whose combined expression values were prognostic of overall survival. The resulting gene expression signature (4-GES) consisted of 4 genes (SOCS2, IL2RA, NPDC1, PHGDH), predicted patient survival as an independent prognostic parameter in several cohorts of AML patients (total, 1272 patients), and further refined prognostication based on the European Leukemia Net classification. An oncogenic role of the top scoring gene in this signature, SOCS2, was investigated using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML. SOCS2 promoted leukemogenesis as well as the abundance, quiescence, and activity of AML stem cells. Overall, the 4-GES represents a highly discriminating prognostic parameter in AML, whose clinical applicability is greatly enhanced by its small number of genes. The newly established role of SOCS2 in leukemia aggressiveness and stemness raises the possibility that the signature might even be exploitable therapeutically.
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http://dx.doi.org/10.1038/s41598-019-45579-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591510PMC
June 2019

Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer.

Br J Haematol 2019 07 9;186(2):311-320. Epub 2019 Apr 9.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Prior studies indicate that neutrophil extracellular traps (NETs) are associated with arterial thromboembolism (ATE) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cell-free DNA [cfDNA], and nucleosomes) and the risk of ATE and all-cause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Nine-hundred and fifty-seven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·7-1·4, P = 0·949), 1·0 per 100 ng/ml (0·9-1·2, P = 0·494) increase and 1·1 per 1-unit increase (1·0-1·2, P = 0·233), respectively. Three-hundred and seventy-eight (39·5%) patients died. The hazard ratio (HR) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·0-1·1, P < 0·001) and 1·1 (1·0-1·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1-unit increase was 1·0 (1·0-1·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.
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http://dx.doi.org/10.1111/bjh.15906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618331PMC
July 2019

DNA methylation of microRNA-coding genes in non-small-cell lung cancer patients.

J Pathol 2018 08 20;245(4):387-398. Epub 2018 Jun 20.

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.

Deregulated DNA methylation leading to transcriptional inactivation of certain genes occurs frequently in non-small-cell lung cancers (NSCLCs). As well as protein-coding genes, microRNA (miRNA)-coding genes may be targets for methylation in NSCLCs; however, the number of known methylated miRNA genes is still small. Thus, we investigated methylation of miRNA genes in primary tumour (TU) samples and corresponding non-malignant lung tissue (NL) samples of 50 NSCLC patients by using methylated DNA immunoprecipitation followed by custom-designed tiling microarray analyses (MeDIP-chip), and 252 differentially methylated probes between TU samples and NL samples were identified. These probes were annotated, which resulted in the identification of 34 miRNA genes with increased methylation in TU samples. Some of these miRNA genes were already known to be methylated in NSCLCs (e.g. those encoding miR-9-3 and miR-124), but methylation of the vast majority of them was previously unknown. We selected six miRNA genes (those encoding miR-10b, miR-1179, miR-137, miR-572, miR-3150b, and miR-129-2) for gene-specific methylation analyses in TU samples and corresponding NL samples of 104 NSCLC patients, and observed a statistically significant increase in methylation of these genes in TU samples (p < 0.0001). In silico target prediction of the six miRNAs identified several oncogenic/cell proliferation-promoting factors (e.g. CCNE1 as an miR-1179 target). To investigate whether miR-1179 indeed targets CCNE1, we transfected miR-1179 gene mimics into CCNE1-expressing NSCLC cells, and observed downregulated CCNE1 mRNA expression in these cells as compared with control cells. Similar effects on cyclin E1 expression were seen in western blot analyses. In addition, we found a statistically significant reduction in the growth of NSCLC cells transfected with miR-1179 mimics as compared with control cells. In conclusion, we identified many methylated miRNA genes in NSCLC patients, and found that the miR-1179 gene is a potential tumour cell growth suppressor in NSCLCs. Overall, our findings emphasize the impact of miRNA gene methylation on the pathogenesis of NSCLCs. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055722PMC
August 2018

Subclinical involvement of the liver is associated with prognosis in treatment naïve cancer patients.

Oncotarget 2017 Oct 16;8(46):81250-81260. Epub 2017 Apr 16.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.

Background: Routinely tested liver biomarkers as alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), butyryl-cholinesterase (BChE), albumin and bilirubin are altered in distinct malignancies and hepatic metastases. This study aimed to investigate whether all liver parameters have the ability to predict long-term mortality in treatment naïve cancer patients but without a malignant hepatic involvement.

Methods: We prospectively enrolled 555 consecutive patients with primary diagnosis of cancer without prior anticancer therapy. BChE, albumin, AST, ALT, GGT and bilirubin as well as the inflammatory makers C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were determined. All-cause mortality was defined as primary endpoint.

Results: During a median follow-up of 25 (IQR16-31) months 186 (34%) patients died. All liver parameters were significantly associated with all-cause mortality (p < 0.001 for all). However, for patients without a malignant primary or secondary hepatic involvement (82%) only the functional parameters BChE and albumin remained significantly associated with the primary endpoint (crude HR per 1-IQR increase 0.61, 95%CI:0.49-0.77; < 0.001 for BChE and 0.58, 95%CI:0.47-0.70; < 0.001 for albumin). This e ect was persistent after multivariate adjustment (adj.HR per 1-IQR increase 0.65, 95%CI:0.50-0.86; p = 0.002 for BChE and 0.63, 95%CI:0.50-0.79; < 0.001 for albumin). BChE and albumin correlated inversely with CRP ( = -0.21, < 0.001 and = -0.36, < 0.001), SAA ( = -0.19, < 0.001 and = -0.33, < 0.001) and IL-6 ( = -0.13, = 0.009 and = -0.17, = 0.001).

Conclusions: Decreased serum BChE and albumin levels are associated with increased all-cause mortality in treatment-naïve cancer patients without a manifest malignant hepatic involvement irrespective of tumor entity or stage. This association may reflect progressing systemic inflammation and metabolic derangement with subclinical involvement of the liver.
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http://dx.doi.org/10.18632/oncotarget.17131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655279PMC
October 2017

Trimodality therapy for Pancoast tumors: T4 is not a contraindication to radical surgery.

J Surg Oncol 2017 Aug 13;116(2):227-235. Epub 2017 Apr 13.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.

Objective: This study aims to evaluate the impact of T stage and extended surgery on the outcome of patients with Pancoast tumors after induction chemoradiation therapy.

Methods: Forty-six consecutive patients who underwent chemoradiation therapy (platin-based, 45-66 Gy) followed by surgery between 1998 and 2013 were retrospectively reviewed and analyzed.

Results: In 28 (61%) patients with T4 tumors, extended procedures (more than rib resection) were performed. There were 37 (80%) lobectomies, 6 (13%) pneumonectomies, and 3 (7%) sublobar resections. A total of 44 (96%) patients had R0 resection. About 30-day mortality was 0%, major surgical complications occurred in 9 (19.6%) patients. Overall survival (OS) at 5-years was 63%. Disease-free survival (DFS) at 5-years was 45%. At multivariate cox regression analysis adjusted for clinical factors, T factor (T3/T4) and extended surgical procedures did not impact survival. However, pathological positive N stage had a negative impact on OS and lack of pathological response negatively impacted both OS and DFS.

Conclusion: Trimodality treatment including radical resection for Pancoast tumors provides good surgical outcome and favorable long-term results. Survival of patients with T4 tumors and extended surgical procedures comparable to that of patients with T3 tumors undergoing rib resection only.
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http://dx.doi.org/10.1002/jso.24629DOI Listing
August 2017

SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers.

Mol Cancer 2017 01 5;16(1). Epub 2017 Jan 5.

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: DNA methylation regulates together with other epigenetic mechanisms the transcriptional activity of genes and is involved in the pathogenesis of malignant diseases including lung cancer. In non-small cell lung cancer (NSCLC) various tumor suppressor genes are already known to be tumor-specifically methylated. However, from the vast majority of a large number of genes which were identified to be tumor-specifically methylated, tumor-specific methylation was unknown so far. Thus, the major aim of this study was to investigate in detail the mechanism(s) responsible for transcriptional regulation of the genes SPAG6 and L1TD1 in NSCLCs.

Methods: We analysed publically available RNA-sequencing data and performed gene expression analyses by RT-PCR. DNA methylation analyses were done by methylation-sensitive high-resolution melt analyses and bisulfite genomic sequencing. We additionally investigated protein expression using immunohistochemistry. Cell culture experiments included tumor cell growth, proliferation, viability as well as colony formation assays. Moreover, we performed xenograft experiments using immunodeficient mice.

Results: We observed frequent downregulation of SPAG6 and L1TD1 mRNA expression in primary tumor (TU) samples compared to corresponding non-malignant lung tissue (NL) samples of NSCLC patients. We furthermore observed re-expression of both genes after treatment with epigenetically active drugs in most NSCLC cell lines with downregulated SPAG6 and L1TD1 mRNA expression. Frequent tumor-specific DNA methylation of SPAG6 and L1TD1 was detected when we analysed TU and corresponding NL samples of NSCLC patients. ROC curve analyses demonstrated that methylation of both genes is able to distinguish between TU and NL samples of these patients. Immunohistochemistry revealed a close association between SPAG6/L1TD1 methylation and downregulated protein expression of these genes. Moreover, by performing functional assays we observed reduced cell growth, proliferation and viability of pCMV6-L1TD1 transfected NSCLC cells. In addition, reduced volumes of tumors derived from pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells were seen in a xenograft tumor model.

Conclusions: Overall, our results demonstrate that SPAG6 and L1TD1 are tumor-specifically methylated in NSCLCs and that DNA methylation is involved in the transcriptional regulation of these genes. Moreover, in vitro as well as in vivo experiments revealed tumor-cell growth suppressing properties of L1TD1 in NSCLC cells.
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http://dx.doi.org/10.1186/s12943-016-0568-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240214PMC
January 2017

The European Society for Medical Oncology Magnitude of Clinical Benefit Scale in daily practice: a single institution, real-life experience at the Medical University of Vienna.

ESMO Open 2016 4;1(4):e000066. Epub 2016 Jul 4.

Clinical Division of Oncology, Department of Medicine I , Comprehensive Cancer Center, Medical University of Vienna-General Hospital , Vienna , Austria.

Background: The European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) has been designed to stratify the therapeutic benefit of a certain drug registered for the treatment of cancer. However, though internally validated, this tool has not yet been evaluated for its feasibility in the daily practice of a major center of medical oncology.

Methods: The practicability of the MCBS for advanced oncological diseases at the Clinical Division of Oncology, Medical University of Vienna, which constitutes one of the largest oncological centres in Europe, was analysed in a three-step approach. First, retrospectively collected data were analysed to gain an overview of treatments in regular use. Second, data were scored by using the MCBS. Third, the ensuing results were evaluated within corresponding programme directorships to assess feasibility in a real-life clinical context.

Results: In the majority of tumour entities, the MCBS results reported earlier are consistent with daily clinical practice. Thus, in metastatic breast cancer or advanced lung cancer, there was a high level of clinical benefit for first-line treatment standards, and these results reflected well real-life experience. However, analyses based on the first version of the MCBS are limited if it comes to salvage treatment in tumour entities in which optimal sequencing of potential treatment options is of major importance, as in metastatic colorectal or renal cell cancer. In contrast to this, it is remarkable that certain novel therapies such as nivolumab assessed for heavily pretreated advanced renal cancer reached the highest level of clinical benefit due to prolongation in survival and a favourable toxicity profile. The MCBS clearly underlines the potential benefit of these compounds.

Conclusions: The MCBS is an excellent tool for daily clinical practice of a tertiary referral centre. It supports treatment decisions based on the clinical benefit to be expected from a novel approach such as immunotherapy in as yet untested indications.
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http://dx.doi.org/10.1136/esmoopen-2016-000066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070236PMC
July 2016

Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

Wien Klin Wochenschr 2016 Sep 25;128(17-18):618-26. Epub 2016 Jul 25.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Treatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033993PMC
http://dx.doi.org/10.1007/s00508-016-1036-3DOI Listing
September 2016

Lung transplantation in patients with incidental early stage lung cancer-institutional experience of a high volume center.

Clin Transplant 2016 08 16;30(8):912-7. Epub 2016 Jun 16.

Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: Incidentally discovered lung cancers in lung transplant (LuTX) recipients are rare but may affect outcome. We aim to report our single center experience with incidence, management, and survival of patients with previously unverified primary lung cancer discovered at the time of LuTX.

Methods: A total of 1262 patients undergoing LuTX between 1989 and 2012 were retrospectively analyzed in our prospective database.

Results: Patients identified were six men and five women with a mean age of 54.4±9.9 years. The indication for LuTX was COPD (n=9), pulmonary fibrosis (n=1), and cystic fibrosis (n=1). Histological diagnosis of the explanted lung revealed adenocarcinoma in six, squamous cell carcinoma in three, and lepidic predominant adenocarcinoma in two cases, respectively. Staging revealed stage IA (pT1a/b pN0) in eight and IB (pT2a pN0) in two cases and one patient in stage IIA (pT1b pN1). Subsequent cancer staging after LuTX revealed no metastasis. Immunosuppression was adjusted and no adjuvant chemo- or radiotherapy was administered. The 5-year survival rate was 90.5% with no detection of recurrence.

Conclusion: In patients with incidentally detected early stage lung cancer at the time of LuTX, rates of recurrence and survival based on this sample appear to be acceptable.
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http://dx.doi.org/10.1111/ctr.12764DOI Listing
August 2016

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

Heart 2015 Dec 28;101(23):1874-80. Epub 2015 Sep 28.

Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Objective: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.

Methods: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint.

Results: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP.

Conclusions: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.
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http://dx.doi.org/10.1136/heartjnl-2015-307848DOI Listing
December 2015

Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma.

J Pathol 2015 Oct 14;237(2):203-14. Epub 2015 Jul 14.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.

Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM.
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http://dx.doi.org/10.1002/path.4567DOI Listing
October 2015

EVI1 promotes tumor growth via transcriptional repression of MS4A3.

J Hematol Oncol 2015 Mar 21;8:28. Epub 2015 Mar 21.

Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: The transcription factor Ecotropic Virus Integration site 1 (EVI1) regulates cellular proliferation, differentiation, and apoptosis, and its overexpression contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells.

Methods: U937T_EVI1, a human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to gene expression profiling. qRT-PCR was used to confirm the regulation of membrane-spanning-4-domains subfamily-A member-3 (MS4A3) by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice.

Results: Gene expression microarray analysis identified 27 unique genes that were up-regulated, and 29 unique genes that were down-regulated, in response to EVI1 induction in the human myeloid cell line U937T. The most strongly repressed gene was MS4A3, and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. MS4A3 mRNA levels were also negatively correlated with those of EVI1 in several published AML data sets. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model by increasing the rate of apoptosis.

Conclusions: Our data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness.
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http://dx.doi.org/10.1186/s13045-015-0124-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389965PMC
March 2015

DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers.

Oncotarget 2015 Jan;6(1):394-408

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria. Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381603PMC
http://dx.doi.org/10.18632/oncotarget.2697DOI Listing
January 2015

CDK6 as a key regulator of hematopoietic and leukemic stem cell activation.

Blood 2015 Jan 23;125(1):90-101. Epub 2014 Oct 23.

Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;

The cyclin-dependent kinase 6 (CDK6) and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (hematopoietic stem cells [HSCs] and leukemic stem cells [LSCs]) that exceeds its function as a cell-cycle regulator. Although hematopoiesis appears normal under steady-state conditions, Cdk6(-/-) HSCs do not efficiently repopulate upon competitive transplantation, and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil treatment. We find that activation of HSCs requires CDK6, which interferes with the transcription of key regulators, including Egr1. Transcriptional profiling of HSCs is consistent with the central role of Egr1. The impaired repopulation capacity extends to BCR-ABL(p210+) LSCs. Transplantation with BCR-ABL(p210+)-infected bone marrow from Cdk6(-/-) mice fails to induce disease, although recipient mice do harbor LSCs. Egr1 knock-down in Cdk6(-/-) BCR-ABL(p210+) LSKs significantly enhances the potential to form colonies, underlining the importance of the CDK6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
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http://dx.doi.org/10.1182/blood-2014-06-584417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281832PMC
January 2015

A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis.

Cancer Cell 2013 Aug;24(2):167-81

Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.

In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6's central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16INK4a.
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http://dx.doi.org/10.1016/j.ccr.2013.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743049PMC
August 2013