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163. Clinical Validation of PITX2 DNA Methylation to Predict Outcome in High-Risk Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy

Author

Schmitt, M. (Manfred), Wilhelm, O.G. (Olaf G.), Noske, A. (Aurelia), Schricker, G. (Gabriele), Napieralski, R., Vetter, M. (Martina), Aubele, M. (Michaela), Perkins, J. (Jonathan), Lauber, J. (Jürgen), Ulm, K. (Kurt), Thomssen, C. (Christoph), Martens, J.W.M. (John), Weichert, W. (Wilko), Kiechle, M. (Marion), Schmitt, M. (Manfred), Wilhelm, O.G. (Olaf G.), Noske, A. (Aurelia), Schricker, G. (Gabriele), Napieralski, R., Vetter, M. (Martina), Aubele, M. (Michaela), Perkins, J. (Jonathan), Lauber, J. (Jürgen), Ulm, K. (Kurt), Thomssen, C. (Christoph), Martens, J.W.M. (John), Weichert, W. (Wilko), and Kiechle, M. (Marion)

Abstract

Background: Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. Methods: The percent DNA methylation ratio (PMR) of the promoter gene coding for the Paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time polymerase chain reaction (PCR) test. The multicenter study was conducted in routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue from 205 lymph node-positive breast cancer patients treated with adjuvant anthracycline-based chemotherapy. Results: The cut-off for the PITX2 methylation status (PMR = 12) was confirmed in a randomly selected cohort (n = 60) and validated (n = 145) prospectively with disease-free survival (DFS) at the 10-year follow-up. DFS was significantly different between the PMR ≤ 12 versus the PMR > 12 group with a hazard ratio (HR) of 2.74 (p < 0.001) in the validation cohort and also for the patient subgroup treated additionally with endocrine therapy (HR 2.47; p = 0.001). Conclusions: Early-stage lymph node-positive breast cancer patients with low PITX2 methylation do benefit from adjuvant anthracycline-based chemotherapy. Patients with a high PITX2 DNA methylation ratio, approximately 30%, show poor outcome and should thus be considered for alternative chemotherapy regimens.

Published
2018
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164. A multi-lake comparative analysis of the General Lake Model (GLM): Stress-testing across a global observatory network

Author

Bruce, L.C., Frassl, Marieke, Arhonditsis, G.B., Gal, G., Hamilton, D.P., Hanson, P.C., Hetherington, A.L., Melack, J.M., Read, J.S., Rinke, Karsten, Rigosi, A., Trolle, D., Winslow, L., Adrian, R., Ayala, A.I., Bocaniov, Serghei, Boehrer, Bertram, Boon, C., Brookes, J.D., Bueche, T., Busch, B.D., Copetti, D., Cortés, A., de Eyto, E., Elliott, J.A., Gallina, N., Gilboa, Y., Guyennon, N., Huang, L., Kerimoglu, O., Lenters, J.D., MacIntyre, S., Makler-Pick, V., McBride, C.G., Moreira, S., Ozkundakci, D., Pilotti, M., Rueda, F.J., Rusak, J.A., Samal, N.R., Schmid, M., Shatwell, T., Snorthheim, C., Soulignac, F., Valerio, G., van der Linden, L., Vetter, M., Vinçon-Leite, B., Wang, J., Weber, Michael, Wickramaratne, C., Woolway, R.I., Yao, H., Hipsey, M.R., Bruce, L.C., Frassl, Marieke, Arhonditsis, G.B., Gal, G., Hamilton, D.P., Hanson, P.C., Hetherington, A.L., Melack, J.M., Read, J.S., Rinke, Karsten, Rigosi, A., Trolle, D., Winslow, L., Adrian, R., Ayala, A.I., Bocaniov, Serghei, Boehrer, Bertram, Boon, C., Brookes, J.D., Bueche, T., Busch, B.D., Copetti, D., Cortés, A., de Eyto, E., Elliott, J.A., Gallina, N., Gilboa, Y., Guyennon, N., Huang, L., Kerimoglu, O., Lenters, J.D., MacIntyre, S., Makler-Pick, V., McBride, C.G., Moreira, S., Ozkundakci, D., Pilotti, M., Rueda, F.J., Rusak, J.A., Samal, N.R., Schmid, M., Shatwell, T., Snorthheim, C., Soulignac, F., Valerio, G., van der Linden, L., Vetter, M., Vinçon-Leite, B., Wang, J., Weber, Michael, Wickramaratne, C., Woolway, R.I., Yao, H., and Hipsey, M.R.

Abstract

The modelling community has identified challenges for the integration and assessment of lake models due to the diversity of modelling approaches and lakes. In this study, we develop and assess a one-dimensional lake model and apply it to 32 lakes from a global observatory network. The data set included lakes over broad ranges in latitude, climatic zones, size, residence time, mixing regime and trophic level. Model performance was evaluated using several error assessment metrics, and a sensitivity analysis was conducted for nine parameters that governed the surface heat exchange and mixing efficiency. There was low correlation between input data uncertainty and model performance and predictions of temperature were less sensitive to model parameters than prediction of thermocline depth and Schmidt stability. The study provides guidance to where the general model approach and associated assumptions work, and cases where adjustments to model parameterisations and/or structure are required.

Published
2018

165. Primary cytomegalovirus infection with accompanying Pneumocystis jiroveci pneumonia in a patient with large-vessel vasculitis

Author

Vetter, M., Battegay, M., Trendelenburg, M., Vetter, M., Battegay, M., and Trendelenburg, M.

Abstract

A 70year-old female patient presented with fever, nausea and dyspnea. She had been receiving immunosuppressive therapy with methotrexate and prednisone for large-vessel vasculitis. The patient was shown to have coexistent Pneumocystis jiroveci pneumonia and primary cytomegalovirus (CMV) infection with presumed CMV pneumonitis and colitis. To our knowledge, this is the first case report on the occurrence of combined primary cytomegalovirus and Pneumocystis jiroveci infection in a patient with vasculitis. It illustrates the importance of being aware of the possibility of combined opportunistic infections in patients with rheumatologic diseases

Published
2018

167. THE AMOUNT OF LIVER TISSUE IS ESSENTIAL FOR ACCURATE HISTOLOGICAL STAGING IN PATIENTS WITH AUTOIMMUNE HEPATITIS.

Author

VETTER, M., KREMER, A. E., AGAIMY, A., KONTUREK, P. C., PFEIFER, L., NEURATH, M. F., SIEBLER, J., and ZOPF, S.

Abstract

The gold standard for the evaluation of liver fibrosis is histology. However, the heterogenous distribution of fibrosis limits the sensitivity of histology. The collection of two samples with a 16G needle is therefore recommended to reduce the risk of sampling error. The aim of this study was to investigate whether this standard is also applicable to patients with autoimmune hepatitis (AIH). This retrospective study included patients with AIH, who underwent mini-laparoscopic biopsy at our center between 2011 and 2020 (n = 32). Diagnosis was verified by usage of the simplified AIH score (³ 6). Patients were categorized into three groups, based on the number of portal fields (PF) in the collected liver tissue (< 10 PF, 10 – 19 PF, ³ 20 PF). We correlated the histological staging for these groups with the mini-laparoscopic fibrosis score (MLFS). Furthermore, non-invasive methods for the assessment of fibrosis were correlated with the histological staging (acoustic radiation force impulse (ARFI) and FIB-4 score). MLFS correlated well with histological staging (r = 0.649, p = 0.0001). The correlation between MLFS and histology improved with higher numbers of histologically analyzed portal fields (< 10 PF: r = 0.400, p = 0.378; 10 – 19 PF: r = 0.5467, p = 0.023; ³ 20 PF: r = 0.956, p = 0.0002). The probability of collecting at least 10 or 20 portal fields was dependent on the number and diameter of the samples. For all patients with at least two 16G biopsies, 10 or more PF were available. With three 16G biopsies, at least 20 PF were obtained for all patients. ARFI correlated with MLFS and histological staging only in patients with low/moderate-grade inflammation as defined by ALT < 10×ULN (upper limit of normal) (MLFS: r = 0.723; p = 0.004; histology: r = 0.619, p = 0.018). FIB4 did not correlate with histological staging. The amount of liver tissue obtained by liver biopsy is crucial to minimalize the risk of sampling error and thus underestimation of fibrosis. This study was the first to investigate the amount of liver tissue required for histological staging in AIH. Our data suggest that diagnostic accuracy is likely to be higher with 20 PF compared to the generally recommended 10 PF. We therefore recommend to perform three biopsies with a 16G needle in (suspected) AIH patients. ARFI correlated well with histological staging unless inflammatory activity is high. [ABSTRACT FROM AUTHOR]

Published
2021
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168. Development and integration of an in-situ framework for visualization of large-scale, unsteady phenomena in ICON

Author

Vetter, M. and Olbrich, S.

Abstract

With large-scale simulation models on massively parallel supercomputers generating increasingly large data sets, in-situ visualization is a promising way to avoid bottlenecks. Enabling in-situ visualization in a simulation model asks for special attention to the interface between a parallel simulation model and the data analysis part of the visualization, and to presentation and interaction scenarios. Modifications to scientific workflows would potentially result in a paradigm shift, which affects compute and data intensive applications generally. We present our approach for enabling in-situ visualization within the highly parallelized climate model ICON using the DSVR visualization framework. We focus on the requirements for generalized grid and data structures, and for universal, scalable algorithms for volume and flow visualization of time series. In-situ pathline extraction as a technique for the visualization of unsteady flows has been integrated in the climate simulation model ICON and verified in first studies.

Published
2017

169. Staging for distant metastases in operable breast cancer: a suggested expansion of the ESMO guideline recommendation for staging imaging of node-negative, hormonal receptor-negative disease

Author

Güth, U., Vetter, M., Huang, D. J., and Heinzelmann-Schwarz, V.

Abstract

We evaluated the impact of staging procedures to detect asymptomatic distant metastases (DM) in the management of women with operable invasive breast cancer (BC, entire cohort: n = 866). Out of 472 patients with lymph node (LN)-negative disease (pN0), DM were found in four cases (detection rate: 0.8%). All four patients presented with established risk factors: hormone receptor (HR)-negative status, HER2-positive status, n = 3; ‘triple-negative' disease, n = 1. Considering the subgroup of LN-negative patients whose tumors showed the risk factor ‘negative HR status' (n = 66), the detection rate of DM was 6%. The detection rates of DM in higher pN categories were as follows: pN1:1.7%; pN2:9.5%; pN3:13.5%. We generally support the international guidelines, including those published by the European Society for Medical Oncology (ESMO) which emphasize that patients with early-stage BC do not profit from radiological staging for the detection of DM and recommend refraining from this. However, we would expand these guidelines and propose that screening should be carried out in node-negative patients whose tumors show established tumor-related risk factors (e.g. HR-negative and HER2-positive status), since in this particular subcohort, the detection rate of DM is with 6% similarly high as that of patients with four to nine positive LNs

Published
2017

183. PITX2 DNA-Methylierung: Erster klinisch validierter prädiktiver Marker zur Vorhersage des Ansprechens auf anthrazyklin-basierte Chemotherapie bei Brustkrebspatientinnen mit hohem Rezidivrisiko

Author

Paepke, S, additional, Wilhelm, OG, additional, Schmitt, M, additional, Noske, A, additional, Schricker, G, additional, Napieralski, R, additional, Vetter, M, additional, Thomssen, C, additional, Perkins, J, additional, Lauber, J, additional, Ulm, K, additional, Martens, JWM, additional, Weichert, W, additional, and Kiechle, M, additional

Published
2018
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185. PITX2 DNA-Methlyierung als klinisch validierter prädiktiver Marker zur Vorhersage des Ansprechens auf Anthrazyklin-haltige Chemotherapie bei Brustkrebspatientinnen mit hohem Rezidivrisiko

Author

Kiechle, M, additional, Wilhelm, O, additional, Paepke, S, additional, Schmitt, M, additional, Noske, A, additional, Schricker, G, additional, Napieralski, R, additional, Vetter, M, additional, Thomssen, C, additional, Perkins, J, additional, Lauber, J, additional, Ulm, K, additional, Martens, JWM, additional, and Weichert, W, additional

Published
2018
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189. International experience of vedolizumab in primary sclerosis cholangitis and inflammatory bowel disease

Author

Williamson, K., primary, Lytvyak, E., additional, Kremer, A.E., additional, de Krijger, M., additional, Trivedi, P., additional, Estes, D., additional, Yu, L., additional, Pratt, D., additional, de Vries, A., additional, Yimam, K.K., additional, Daretti, L., additional, Liu, C.H., additional, Bowlus, C., additional, Vetter, M., additional, Marschall, H.-U., additional, Montano-Loza, A., additional, Chapman, R.W.G., additional, Marzioni, M., additional, Keshav, S., additional, Ponsioen, C., additional, Hirschfield, G., additional, and Levy, C., additional

Published
2018
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192. n-type emitter surface passivation in c-Si solar cells by means of antireflective amorphous silicon carbide layers.

Author

Ferre, R., Martín, I., Ortega, P., Vetter, M., Torres, I., and Alcubilla, R.

Subjects
SILICON solar cells, SILICON carbide, AMORPHOUS substances, PHOSPHORUS, DIFFUSION
Abstract

Emitter saturation current densities (JOe) of phosphorus-diffused planar c-Si solar cell emitters passivated by silicon carbide (SiCx) layers have been determined in a wide sheet resistance range (20–500 Ω/sq). Phosphorus diffusions were performed using solid planar diffusion sources without employing any drive-in step. Stacks of two SiCx layers were deposited by plasma enhanced chemical vapor deposition: first a thin silicon rich layer with excellent passivating properties and then an antireflective carbon rich layer. The thickness of the passivating layer was optimized, reaching a trade-off between the better passivation achieved for thicker layers and the increased light absorption within the layer, which reduced the photocurrent. The surface recombination velocity and the optical losses were determined for each configuration and used to calculate photovoltaic conversion efficiency limits for 50 and 90 Ω/sq emitters. In both cases, optimum configuration is for the stacks with passivating layers that are about 8 nm thick. [ABSTRACT FROM AUTHOR]

Published
2006
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193. Crystalline silicon surface passivation with amorphous SiCx:H films deposited by plasma-enhanced chemical-vapor deposition.

Author

Martín, I., Vetter, M., Garín, M., Orpella, A., Voz, C., Puigdollers, J., and Alcubilla, R.

Subjects
*SILICON carbide thin films, *SURFACES (Physics), *AMORPHOUS semiconductors, *CHEMICAL vapor deposition, *SEMICONDUCTORS, *THIN films, *VAPOR-plating, *SURFACE chemistry
Abstract

Surface-passivating properties of hydrogenated amorphous silicon carbide films (a-SiCx:H) deposited by plasma-enhanced chemical-vapor deposition on both p- and n-type crystalline silicon (c-Si) have been extensively studied by our research group in previous publications. We characterized surface recombination by measuring the dependence of the effective lifetime (τeff) on excess carrier density (Δn) through quasi-steady-state photoconductance technique. Additionally, we fitted the measured τeff(Δn) curves applying an insulator/semiconductor model which allows us to determine the surface recombination parameters. In this paper, this model is analyzed in detail focusing on the accuracy in the determination of the fitting parameters and revealing uncertainties not detected up to now. Taking advantage of this analysis, the dependence of surface passivation on film deposition conditions is revised including intrinsic a-SiCx:H films on both p- and n-type c-Si and phosphorus-doped a-SiCx:H films on p-type c-Si. As a consequence, a broad view of this passivation scheme is obtained. [ABSTRACT FROM AUTHOR]

Published
2005
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198. Microcrystalline testing used in combination with Raman micro-spectroscopy for absolute identification of novel psychoactive substances

Author

Elie, L, Elie, M, Cave, G, Vetter, M, Croxton, R, and Baron, M

Subjects
B200 Pharmacology, Toxicology and Pharmacy
Abstract

Two new psychoactive substances, namely 4-methylmethcathinone (mephedrone) and 5,6-methylenedioxy-2-aminoindane (MDAI) were analysed with a novel combination of microcrystalline tests followed by Raman micro-spectroscopy to facilitate their absolute identification. The discrimination power of the proposed combination was successfully demonstrated through the analysis of the positional isomers 2- and 3-methylmethcathinone. The addition of mercury dichloride as a microcrystalline test reagent produced specific microcrystals of each tested analyte. The robustness of the method was evaluated in the presence of common cutting agents (caffeine and benzocaine) as well as on street samples. The crystal lattice structures of mephedrone, 2-methylmethcathinone and MDAI mercury dichloride microcrystals were determined by single crystal X-ray diffraction. This confirmed the presence of both drug and reagent together in the lattice and accounts for the distinct habit of the observed microcrystals. Raman spectra of the formed microcrystals differed from those obtained from their standard salt form by loss and/or gain of some vibrational modes. Particularly important was the appearance of the mercury chloride link to each tested drug molecule which showed as strong bands at low wavenumbers. Its presence was corroborated by its detection in the crystal lattice. It was therefore concluded that microcrystalline testing followed by Raman micro-spectroscopy satisfies the technique combination requirement for psychoactive substances recommended by the Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG) and provides a rapid and cheap analysis route. The proposed technique combination also aids the development of new microcrystalline tests as it allows for confirmation of the uniqueness of the developed microcrystals almost in-situ rather than growing single crystals for often long periods of time needed for single crystal X-ray diffraction analysis. Copyright © 2016 John Wiley & Sons, Ltd.

Published
2016

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