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1. Detection and localization of early- and late-stage cancers using platelet RNA

Author

Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., Sistermans, E.A., Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., and Sistermans, E.A.

Abstract

Contains fulltext : 281792.pdf (Publisher’s version ) (Open Access), Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Published
2022

2. TP53 is not a prognostic marker-clinical consequences of a generally disregarded fact

Author

Braunschmid, T, Kuehrer, I, Mittlboeck, M, Westerhoff, M, Kappel-Latif, S, Brammen, L, Krishnadath, KK, Phillips, WA, Gnant, M, Kandioler, D, Braunschmid, T, Kuehrer, I, Mittlboeck, M, Westerhoff, M, Kappel-Latif, S, Brammen, L, Krishnadath, KK, Phillips, WA, Gnant, M, and Kandioler, D

Abstract

Technological progress within the last 15-20 years has significantly increased our knowledge about the molecular basis of cancer development, tumor progression, and treatment response. As a consequence, a vast number of biomarkers have been proposed, but only a small fraction of them have found their way into clinical use. The aim of this paper is to describe the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. We name this procedure the "triple-R principle": robustness, reproducibility, and relevance. The usefulness of this principle is illustrated with the marker TP53. Since it is mutated in a broad spectrum of cancer entities, TP53 can be considered a very promising marker. Thus, TP53 has been studied in detail but there is still no explicit consensus about its clinical value. By considering our own experience and reviewing the literature, we demonstrate that a major problem of current biomarker research is disregard of whether the biomarker is prognostic or predictive. As an example, it is demonstrated that TP53 is not a prognostic marker, but rather a purely predictive marker, and that disregard of this fact has made this otherwise strong biomarker appear as not being clinically useful so far.

Published
2018

3. Is (18)F-FDG PET really a promising marker for clinically relevant atherosclerosis?

Author

Brammen, L, Palumbo, Barbara, Lupattelli, Graziana, and Sinzinger, H.

Subjects
PLAQUES, POSITRON-EMISSION-TOMOGRAPHY, CALCIFICATIONS, ARTERIES, INVIVO, VASCULAR INFLAMMATION, WALL, FDG-PET, ACCUMULATION, LDL
Abstract

Bural et al (2013), retrospectively investigated 143 subjects who received whole body fluorine-18-fluorodeoxyglucose- positron emission tomography ((18)F-FDG-PET) imaging for the assessment of non-cardiovascular diseases. They reported an increase of (18)F-FDG-positive lesions in various aortic segments, which increased with age, and were more pronounced in subjects being aged below 50 years as compared to those above 50. Bural et al also found the highest segmental (18)F-FDG-uptake in the descending thoracic aorta, but not in the abdominal aorta, where the majority of the most severe atherosclerotic lesions essentially appear. In addition, they did not appreciate any significant gender difference. Despite the severe limitation that no correlation to vascular disease, risk factors, or any clinical parameter was available, this report again raises the question as to what positive (18)F-FDG imaging really reflects and whether it will ever reach the great expectations. Conventional radiotracers revealed an excellent experimental correlation, as well as morphology. Uptake ratios of symptomatic lesion vs. contralateral unaffected side were comparable between (111)In-platelets, (123)I-LDL and (18)FFDG. There was also a mass strategic correlation, but no individual prediction of events at all. Due to better statistics, image quality and solution PET imaging of atherosclerosis holds great promise. However, correlations between various tracers and vascular wall characteristics (and staining methodologies) in 1% cholesterol fed rabbits reveal that (18)F-FDG is not always the best tracer. Vascular foam cell content is reflected by (111)In-HIG(125)I-oxLp(a)(18)F-FDG(125)I-LDL (Brammen L, Palumbo B, Lupattelli G et al. Unpublished data). A close correlation to Framingham risk score is for example not helpful, as this score has a low predictive value of only 0.6. The available clinical correlations between (18)F-FDG-uptake and arterial wall characteristics are poor. For example, Lederman RJ et al (2001) reported a correlation between (18)FFDG uptake with intima/media ratio, whereas no correlation was established in a paper by Ogawa M et al (2004). On the other hand, Laitinen I et al (2006) described a correlation between (18)F-FDG-uptake and calcifications, however, Tatsumi M et al (2003) did not observe this in his paper. The claim that inflammation and macrophage uptake of (18)F-FDG may be able to characterize and identify early atherosclerotic lesions has never been substantiated. Earlier studies reveal a negative correlation between (18)F-FDG uptake and smooth muscle cells, but a positive one with macrophages. The extent of uptake by different vascular wall cells (e.g. endothelial cells, smooth muscle cells, macrophages) in different atherosclerotic lesion types under various biochemical conditions has thus far not been extensively studied, neither in vitro nor in experimental or clinical work. Only one recent report does deal with this issue. Our preliminary studies show that the cellular uptake extremely varies depending on the local metabolic condition. For example, smooth muscle and endothelial cells, when exposed to pro-inflammatory cytokines, exhibit an extremely enhanced (18)F-FDG uptake while local hypoxia results in an opposite behavior. This is not observed in macrophages. Furthermore, when cultured cells were studied, uptake was severely dependent on the duration of incubation and the type of stimulation. This data indicates that (18)F-FDG uptake is enhanced in early foam cell formation, as well as in activated smooth muscle cells that eventually reach, under certain conditions, a comparable uptake. In addition, there is a lack of standardization and of prospective studies preventing reliable clinical interpretation. There seems to be only one consensus. There is no abnormal uptake of (18)F-FDG as well as of conventional tracers in the intact vascular wall and intra individual therapeutic intervention is truly reflected. The goal of non-invasive imaging in humans is to identify plaques at risk, an active lesion or the extent of the disease. As long as no prospective controlled data with other imaging modalities identifying vascular alterations defined per lesion and not per segment are available, it seems very unlikely that (18)F-FDG may significantly succeed in this particular indication.

Published
2014

5. Abstracts

Author

Dunet, V., primary, Dabiri, A., additional, Allenbach, G., additional, Goyeneche Achigar, A., additional, Waeber, B., additional, Feihl, F., additional, Heinzer, R., additional, Prior, J. O., additional, Van Velzen, J. E., additional, Schuijf, J. D., additional, De Graaf, F. R., additional, De Graaf, M. A., additional, Schalij, M. J., additional, Kroft, L. J., additional, De Roos, A., additional, Jukema, J. W., additional, Van Der Wall, E. E., additional, Bax, J. J., additional, Lankinen, E., additional, Saraste, A., additional, Noponen, T., additional, Klen, R., additional, Teras, M., additional, Kokki, T., additional, Kajander, S., additional, Pietila, M., additional, Ukkonen, H., additional, Knuuti, J., additional, Pazhenkottil, A. P., additional, Nkoulou, R. N., additional, Ghadri, J. R., additional, Herzog, B. A., additional, Buechel, R. R., additional, Kuest, S. M., additional, Wolfrum, M., additional, Gaemperli, O., additional, Husmann, L., additional, Kaufmann, P. A., additional, Andreini, D., additional, Pontone, G., additional, Mushtaq, S., additional, Antonioli, L., additional, Bertella, E., additional, Formenti, A., additional, Cortinovis, S., additional, Ballerini, G., additional, Fiorentini, C., additional, Pepi, M., additional, Koh, A. S., additional, Flores, J. S., additional, Keng, F. Y. J., additional, Tan, R. S., additional, Chua, T. S. J., additional, Annoni, A. D., additional, Tamborini, G., additional, Fusari, M., additional, Bartorelli, A. L., additional, Ewe, S. H., additional, Ng, A. C. T., additional, Delgado, V., additional, Schuijf, J., additional, Van Der Kley, F., additional, Colli, A., additional, De Weger, A., additional, Marsan, N. A., additional, Yiu, K. H., additional, Ng, A. C., additional, Timmer, S. A. J., additional, Knaapen, P., additional, Germans, T., additional, Dijkmans, P. A., additional, Lubberink, M., additional, Ten Berg, J. M., additional, Ten Cate, F. J., additional, Russel, I. K., additional, Lammertsma, A. A., additional, Van Rossum, A. C., additional, Wong, Y. Y., additional, Ruiter, G., additional, Raijmakers, P., additional, Van Der Laarse, W. J., additional, Westerhof, N., additional, Vonk-Noordegraaf, A., additional, Youssef, G., additional, Leung, E., additional, Wisenberg, G., additional, Marriot, C., additional, Williams, K., additional, Etele, J., additional, Dekemp, R. A., additional, Dasilva, J., additional, Birnie, D., additional, Beanlands, R. S. B., additional, Thompson, R. C., additional, Allam, A. H., additional, Wann, L. S., additional, Nureldin, A. H., additional, Adelmaksoub, G., additional, Badr, I., additional, Sutherland, M. L., additional, Sutherland, J. D., additional, Miyamoto, M. I., additional, Thomas, G. S., additional, Harms, H. J., additional, De Haan, S., additional, Huisman, M. C., additional, Schuit, R. C., additional, Windhorst, A. D., additional, Allaart, C., additional, Einstein, A. J., additional, Khawaja, T., additional, Greer, C., additional, Chokshi, A., additional, Jones, M., additional, Schaefle, K., additional, Bhatia, K., additional, Shimbo, D., additional, Schulze, P. C., additional, Srivastava, A., additional, Chettiar, R., additional, Moody, J., additional, Weyman, C., additional, Natale, D., additional, Bruni, W., additional, Liu, Y., additional, Ficaro, E., additional, Sinusas, A. J., additional, Peix, A., additional, Batista, E., additional, Cabrera, L. O., additional, Padron, K., additional, Rodriguez, L., additional, Sainz, B., additional, Mendoza, V., additional, Carrillo, R., additional, Fernandez, Y., additional, Mena, E., additional, Naum, A., additional, Bach-Gansmo, T., additional, Kleven-Madsen, N., additional, Biermann, M., additional, Johnsen, B., additional, Aase Husby, J., additional, Rotevatn, S., additional, Nordrehaug, J. E., additional, Schaap, J., additional, Kauling, R. M., additional, Post, M. C., additional, Rensing, B. J. W. M., additional, Verzijlbergen, J. F., additional, Sanchez, J., additional, Giamouzis, G., additional, Tziolas, N., additional, Georgoulias, P., additional, Karayannis, G., additional, Chamaidi, A., additional, Zavos, N., additional, Koutrakis, K., additional, Sitafidis, G., additional, Skoularigis, J., additional, Triposkiadis, F., additional, Radovanovic, S., additional, Djokovic, A., additional, Simic, D. V., additional, Krotin, M., additional, Savic-Radojevic, A., additional, Pljesa-Ercegovac, M., additional, Zdravkovic, M., additional, Saponjski, J., additional, Jelic, S., additional, Simic, T., additional, Eckardt, R., additional, Kjeldsen, B. J., additional, Andersen, L. I., additional, Haghfelt, T., additional, Grupe, P., additional, Johansen, A., additional, Hesse, B., additional, Pena, H., additional, Cantinho, G., additional, Wilk, M., additional, Srour, Y., additional, Godinho, F., additional, Zafrir, N., additional, Gutstein, A., additional, Mats, I., additional, Battler, A., additional, Solodky, A., additional, Sari, E., additional, Singh, N., additional, Vara, A., additional, Peters, A. M., additional, De Belder, A., additional, Nair, S., additional, Ryan, N., additional, James, R., additional, Dizdarevic, S., additional, Depuey, G., additional, Friedman, M., additional, Wray, R., additional, Old, R., additional, Babla, H., additional, Chuanyong, B., additional, Maddahi, J., additional, Tragardh Johansson, E., additional, Sjostrand, K., additional, Edenbrandt, L., additional, Aguade-Bruix, S., additional, Cuberas-Borros, G., additional, Pizzi, M. N., additional, Sabate-Fernandez, M., additional, De Leon, G., additional, Garcia-Dorado, D., additional, Castell-Conesa, J., additional, Candell-Riera, J., additional, Casset-Senon, D., additional, Edjlali-Goujon, M., additional, Alison, D., additional, Delhommais, A., additional, Cosnay, P., additional, Low, C. S., additional, Notghi, A., additional, O'brien, J., additional, Tweddel, A. C., additional, Bingham, N., additional, O Neil, P., additional, Harbinson, M., additional, Lindner, O., additional, Burchert, W., additional, Schaefers, M., additional, Marcassa, C., additional, Campini, R., additional, Calza, P., additional, Zoccarato, O., additional, Kisko, A., additional, Kmec, J., additional, Babcak, M., additional, Vereb, M., additional, Vytykacova, M., additional, Cencarik, J., additional, Gazdic, P., additional, Stasko, J., additional, Abreu, A., additional, Pereira, E., additional, Oliveira, L., additional, Colarinha, P., additional, Veloso, V., additional, Enriksson, I., additional, Proenca, G., additional, Delgado, P., additional, Rosario, L., additional, Sequeira, J., additional, Kosa, I., additional, Vassanyi, I., additional, Egyed, C. S., additional, Kozmann, G. Y., additional, Morita, S., additional, Nanasato, M., additional, Nanbu, I., additional, Yoshida, Y., additional, Hirayama, H., additional, Allam, A., additional, Sharef, A., additional, Shawky, I., additional, Farid, M., additional, Mouden, M., additional, Ottervanger, J. P., additional, Timmer, J. R., additional, De Boer, M. J., additional, Reiffers, S., additional, Jager, P. L., additional, Knollema, S., additional, Nasr, G. M., additional, Mohy Eldin, M., additional, Ragheb, M., additional, Casans-Tormo, I., additional, Diaz-Exposito, R., additional, Hurtado-Mauricio, F. J., additional, Ruano, R., additional, Diego, M., additional, Gomez-Caminero, F., additional, Albarran, C., additional, Martin De Arriba, A., additional, Rosero, A., additional, Lopez, R., additional, Martin Luengo, C., additional, Garcia-Talavera, J. R., additional, Laitinen, I. E. K., additional, Rudelius, M., additional, Weidl, E., additional, Henriksen, G., additional, Wester, H. J., additional, Schwaiger, M., additional, Pan, X. B., additional, Schindler, T., additional, Quercioli, A., additional, Zaidi, H., additional, Ratib, O., additional, Declerck, J. M., additional, Alexanderson Rosas, E., additional, Jacome, R., additional, Jimenez-Santos, M., additional, Romero, E., additional, Pena-Cabral, M. A., additional, Meave, A., additional, Gonzalez, J., additional, Rouzet, F., additional, Bachelet, L., additional, Alsac, J. M., additional, Suzuki, M., additional, Louedec, L., additional, Petiet, A., additional, Chaubet, F., additional, Letourneur, D., additional, Michel, J. B., additional, Le Guludec, D., additional, Aktas, A., additional, Cinar, A., additional, Yaman, G., additional, Bahceci, T., additional, Kavak, K., additional, Gencoglu, A., additional, Jimenez-Heffernan, A., additional, Sanchez De Mora, E., additional, Lopez-Martin, J., additional, Lopez-Aguilar, R., additional, Ramos, C., additional, Salgado, C., additional, Ortega, A., additional, Sanchez-Gonzalez, C., additional, Roa, J., additional, Tobaruela, A., additional, Nesterov, S. V., additional, Turta, O., additional, Maki, M., additional, Han, C., additional, Daou, D., additional, Tawileh, M., additional, Chamouine, S. O., additional, Coaguila, C., additional, Mariscal-Labrador, E., additional, Kisiel-Gonzalez, N., additional, De Araujo Goncalves, P., additional, Sousa, P. J., additional, Marques, H., additional, O'neill, J., additional, Pisco, J., additional, Cale, R., additional, Brito, J., additional, Gaspar, A., additional, Machado, F. P., additional, Roquette, J., additional, Martinez, M., additional, Melendez, G., additional, Kimura, E., additional, Ochoa, J. M., additional, Alessio, A. M., additional, Patel, A., additional, Lautamaki, R., additional, Bengel, F. M., additional, Bassingthwaighte, J. B., additional, Caldwell, J. H., additional, Rahbar, K., additional, Seifarth, H., additional, Schafers, M., additional, Stegger, L., additional, Spieker, T., additional, Hoffmeier, A., additional, Maintz, D., additional, Scheld, H., additional, Schober, O., additional, Weckesser, M., additional, Aoki, H., additional, Matsunari, I., additional, Kajinami, K., additional, Martin Fernandez, M., additional, Barreiro Perez, M., additional, Fernandez Cimadevilla, O. V., additional, Leon Duran, D., additional, Velasco Alonso, E., additional, Florez Munoz, J. P., additional, Luyando, L. H., additional, Templin, C., additional, Veltman, C. E., additional, Reiber, J. H. C., additional, Venuraju, S., additional, Yerramasu, A., additional, Atwal, S., additional, Lahiri, A., additional, Kunimasa, T., additional, Shiba, M., additional, Ishii, K., additional, Aikawa, J., additional, Kroner, E. S. J., additional, Ho, K. T., additional, Yong, Q. W., additional, Chua, K. C., additional, Panknin, C., additional, Roos, C. J., additional, Van Werkhoven, J. M., additional, Witkowska-Grzeslo, A. J., additional, Boogers, M. J., additional, Anand, D. V., additional, Dey, D., additional, Berman, D., additional, Mut, F., additional, Giubbini, R., additional, Lusa, L., additional, Massardo, T., additional, Iskandrian, A., additional, Dondi, M., additional, Sato, A., additional, Kakefuda, Y., additional, Ojima, E., additional, Adachi, T., additional, Atsumi, A., additional, Ishizu, T., additional, Seo, Y., additional, Hiroe, M., additional, Aonuma, K., additional, Kruk, M., additional, Pracon, R., additional, Kepka, C., additional, Pregowski, J., additional, Kowalewska, A., additional, Pilka, M., additional, Opolski, M., additional, Michalowska, I., additional, Dzielinska, Z., additional, Demkow, M., additional, Stoll, V., additional, Sabharwal, N., additional, Chakera, A., additional, Ormerod, O., additional, Fernandes, H., additional, Bernardes, M., additional, Martins, E., additional, Oliveira, P., additional, Vieira, T., additional, Terroso, G., additional, Oliveira, A., additional, Faria, T., additional, Ventura, F., additional, Pereira, J., additional, Fukuzawa, S., additional, Inagaki, M., additional, Sugioka, J., additional, Ikeda, A., additional, Okino, S., additional, Maekawa, J., additional, Uchiyama, T., additional, Kamioka, N., additional, Ichikawa, S., additional, Afshar, M., additional, Alvi, R., additional, Aguilar, N., additional, Ippili, R., additional, Shaqra, H., additional, Bella, J., additional, Bhalodkar, N., additional, Dos Santos, A., additional, Daicz, M., additional, Cendoya, L. O., additional, Marrero, H. G., additional, Casuscelli, J., additional, Embon, M., additional, Vera Janavel, G., additional, Duronto, E., additional, Gurfinkel, E. P., additional, Cortes, C. M., additional, Takeishi, Y., additional, Nakajima, K., additional, Yamasaki, Y., additional, Nishimura, T., additional, Hayes Brown, K., additional, Collado, F., additional, Alhaji, M., additional, Green, J., additional, Alexander, S., additional, Vashistha, R., additional, Jain, S., additional, Aldaas, F., additional, Shanes, J., additional, Doukky, R., additional, Ashikaga, K., additional, Akashi, Y. J., additional, Uemarsu, M., additional, Kamijima, R., additional, Yoneyama, K., additional, Omiya, K., additional, Miyake, Y., additional, Brodov, Y., additional, Raval, U., additional, Berezin, A., additional, Seden, V., additional, Koretskaya, E., additional, Panasenko, T. A., additional, Matsuo, S., additional, Kinuya, S., additional, Chen, J., additional, Van Bommel, R. J., additional, Van Der Hiel, B., additional, Dibbets-Schneider, P., additional, Garcia, E. V., additional, Rutten-Vermeltfoort, I., additional, Gevers, M. M. J., additional, Verhoeven, B., additional, Dijk Van, A. B., additional, Raaijmakers, E., additional, Raijmakers, P. G. H. M., additional, Engvall, J. E., additional, Gjerde, M., additional, De Geer, J., additional, Olsson, E., additional, Quick, P., additional, Persson, A., additional, Mazzanti, M., additional, Marini, M., additional, Pimpini, L., additional, Perna, G. P., additional, Marciano, C., additional, Gargiulo, P., additional, Galderisi, M., additional, D'amore, C., additional, Savarese, G., additional, Casaretti, L., additional, Paolillo, S., additional, Cuocolo, A., additional, Perrone Filardi, P., additional, Al-Amoodi, M., additional, Thompson, E. C., additional, Kennedy, K., additional, Bybee, K. A., additional, Mcghie, A. I., additional, O'keefe, J. H., additional, Bateman, T. M., additional, Van Der Palen, R. L. F., additional, Mavinkurve-Groothuis, A. M., additional, Bulten, B., additional, Bellersen, L., additional, Van Laarhoven, H. W. M., additional, Kapusta, L., additional, De Geus-Oei, L. F., additional, Pollice, P. P., additional, Bonifazi, M. B., additional, Pollice, F. P., additional, Clements, I. P., additional, Hodge, D. O., additional, Scott, C. G., additional, De Ville De Goyet, M., additional, Brichard, B., additional, Pirotte, T., additional, Moniotte, S., additional, Tio, R. A., additional, Elvan, A., additional, Dierckx, R. A. I. O., additional, Slart, R. H. J. 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2011
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8. Detection and localization of early- and late-stage cancers using platelet RNA.

Author

In 't Veld SGJG, Arkani M, Post E, Antunes-Ferreira M, D'Ambrosi S, Vessies DCL, Vermunt L, Vancura A, Muller M, Niemeijer AN, Tannous J, Meijer LL, Le Large TYS, Mantini G, Wondergem NE, Heinhuis KM, van Wilpe S, Smits AJ, Drees EEE, Roos E, Leurs CE, Tjon Kon Fat LA, van der Lelij EJ, Dwarshuis G, Kamphuis MJ, Visser LE, Harting R, Gregory A, Schweiger MW, Wedekind LE, Ramaker J, Zwaan K, Verschueren H, Bahce I, de Langen AJ, Smit EF, van den Heuvel MM, Hartemink KJ, Kuijpers MJE, Oude Egbrink MGA, Griffioen AW, Rossel R, Hiltermann TJN, Lee-Lewandrowski E, Lewandrowski KB, De Witt Hamer PC, Kouwenhoven M, Reijneveld JC, Leenders WPJ, Hoeben A, Verdonck-de Leeuw IM, Leemans CR, Baatenburg de Jong RJ, Terhaard CHJ, Takes RP, Langendijk JA, de Jager SC, Kraaijeveld AO, Pasterkamp G, Smits M, Schalken JA, Łapińska-Szumczyk S, Łojkowska A, Żaczek AJ, Lokhorst H, van de Donk NWCJ, Nijhof I, Prins HJ, Zijlstra JM, Idema S, Baayen JC, Teunissen CE, Killestein J, Besselink MG, Brammen L, Bachleitner-Hofmann T, Mateen F, Plukker JTM, Heger M, de Mast Q, Lisman T, Pegtel DM, Bogaard HJ, Jassem J, Supernat A, Mehra N, Gerritsen W, de Kroon CD, Lok CAR, Piek JMJ, Steeghs N, van Houdt WJ, Brakenhoff RH, Sonke GS, Verheul HM, Giovannetti E, Kazemier G, Sabrkhany S, Schuuring E, Sistermans EA, Wolthuis R, Meijers-Heijboer H, Dorsman J, Oudejans C, Ylstra B, Westerman BA, van den Broek D, Koppers-Lalic D, Wesseling P, Nilsson RJA, Vandertop WP, Noske DP, Tannous BA, Sol N, Best MG, and Wurdinger T

Subjects
Biomarkers, Tumor genetics, Blood Platelets, Early Detection of Cancer methods, Humans, Neoplasms diagnosis, Neoplasms genetics, RNA genetics
Abstract

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2022
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9. Outcome in Patients Treated With Cytoreductive Surgery and HIPEC for Gastric Cancer With Peritoneal Carcinomatosis.

Author

Braeuer F, Fischer I, Brammen L, Pressl G, Fuegger R, Rohregger K, and Wundsam H

Subjects
Aged, Combined Modality Therapy, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Peritoneal Neoplasms complications, Retrospective Studies, Stomach Neoplasms complications, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytoreduction Surgical Procedures methods, Hyperthermia, Induced methods, Peritoneal Neoplasms therapy, Stomach Neoplasms therapy
Abstract

Background/aim: We compared patients with advanced gastric cancer [Union for International Cancer Control (UICC) III] versus patients with stage UICC IV and peritoneal carcinomatosis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) versus patients with stage UICC IV treated without HIPEC to ascertain if CRS and HIPEC improve overall survival (OS)., Patients and Methods: We retrospectively analysed thirty-seven advanced gastric cancer patients who had been treated at our department from 2012 to 2017. The endpoint was median OS., Results: Eighteen (49%) patients with UICC stage III showed a median OS of 37.4 months. Eight (21%) patients in the HIPEC group reached a median OS of 33.8 months. Median OS in the UICC IV group (11 patients, 30%) treated with a palliative concept was 6.2 months and therefore significantly worse (p=0.004)., Conclusion: A systemic approach combined with CRS and HIPEC in selected stage IV gastric cancer patients improves the OS comparable to patients in UICC stage III., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Published
2020
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10. Efficacy of calcium excretion and calcium/creatinine clearance ratio in the differential diagnosis of familial hypocalciuric hypercalcemia and primary hyperparathyroidism.

Author

Bhangu JS, Selberherr A, Brammen L, Scheuba C, and Riss P

Subjects
Adult, Aged, Cohort Studies, Diagnosis, Differential, Female, Follow-Up Studies, Humans, Hypercalcemia blood, Hypercalcemia diagnosis, Hypercalcemia surgery, Hyperparathyroidism, Primary blood, Hyperparathyroidism, Primary surgery, Male, Middle Aged, Parathyroid Hormone blood, Prospective Studies, Risk Assessment, Treatment Outcome, Calcium urine, Creatinine urine, Hypercalcemia congenital, Hyperparathyroidism, Primary diagnosis, Parathyroidectomy methods
Abstract

Background: Twenty-four-hour renal calcium-excretion (CE) and calcium/creatinine-clearance-ratio (CCCR), respectively, are widely used to rule out familial hypocalciuric hypercalcemia (FHH) in patients with suspected primary hyperparathyroidism before surgery. The aim was to evaluate the practicability of CE compared to CCCR., Patients and Methods: We analyzed biochemical parameters, surgical treatment, gene mutation results, and long-term follow-up data of 198 patients (including 14 patients with FHH) and the discriminative power of CE and CCCR., Results: Twenty four patients (12.1%) had a low CE and 35 patients (20.2%) had a CCCR indicating FHH. However, eight patients with FHH (57.1%) had a normal or increased CE. Correspondingly, only eight cases of FHH (57.1%) were correctly predicted by CCCR. Sensitivity/specificity were 42.9%/89.9% for CE and 64.3%/79.9% for CCCR, showing no statistical differences (P = 0.482) between both methods., Conclusion: Neither CE nor CCCR was able to distinguish between PHPT and FHH but may help to narrow down potential FHH patients., (© 2018 Wiley Periodicals, Inc.)

Published
2019
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11. Evaluating a shortened interpretation criterion for intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism: 5-minutes criterion in primary hyperparathyroidism and intraoperative algorithm.

Author

Riss P, Dunkler D, Selberherr A, Brammen L, Heidtmann J, and Scheuba C

Subjects
False Negative Reactions, Feasibility Studies, Female, Humans, Hyperparathyroidism, Primary blood, Male, Middle Aged, Minimally Invasive Surgical Procedures, Predictive Value of Tests, Retrospective Studies, Sensitivity and Specificity, Time Factors, Algorithms, Hyperparathyroidism, Primary surgery, Monitoring, Intraoperative methods, Operative Time, Parathyroid Hormone blood, Parathyroidectomy methods
Abstract

Background: Most criteria require a parathyroid hormone (PTH) decline of ≥50% within 10 minutes after excision of the gland during surgery for primary hyperparathyroidism. The aim was to evaluate a model allowing earlier prediction of cure., Methods: One thousand eighteen patients with primary hyperparathyroidism were included. A ≥50% decline from baseline within 10 minutes after excision intraoperatively predicted complete removal of hypersecreting tissue. The data were reanalyzed regarding a criterion, requiring a ≥50% decline after 5 minutes. Based on the data and the present literature, an algorithm was created., Results: Assay predicted cure in 854 patients (true-positive; 83.89%) after 10 minutes (false-positive [FP] in 13 patients; 1.52%). Nevertheless, only 14 (1.83%) showed persisting disease. According to the "5 minutes" criterion, 723 patients (71.02%) showed a ≥50% decline from baseline within 5 minutes and 10 (1.38%) patients had a FP decline (sensitivity 0.75, specificity 0.86)., Conclusion: Using a modified criterion, surgery can be discontinued 5 minutes earlier in 71%., (© 2018 Wiley Periodicals, Inc.)

Published
2018
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12. How radical is total parathyroidectomy in patients with renal hyperparathyroidism?

Author

Burgstaller T, Selberherr A, Brammen L, Scheuba C, Kaczirek K, and Riss P

Subjects
Adult, Aged, Female, Humans, Hyperparathyroidism, Secondary complications, Kidney Failure, Chronic complications, Male, Middle Aged, Neck Dissection, Parathyroid Hormone blood, Retrospective Studies, Thymectomy, Treatment Outcome, Hyperparathyroidism, Secondary surgery, Parathyroidectomy
Abstract

Purpose: Total parathyroidectomy (tPTX) in patients with renal hyperparathyroidism (RHPT) aims at the complete removal of all hyperfunctioning parathyroid tissue. Whenever parathyroidectomy is termed "total," undetectable postoperative parathyroid hormone (PTH) levels within the first postoperative week are expected. The aim of this study was to evaluate if tPTX is technically possible using a radical surgical procedure., Methods: In 109 consecutive patients with RHPT (on hemodialysis: n = 50; after kidney grafting n = 59), removal of all visible parathyroid tissue, bilateral thymectomy, bilateral central neck dissection (level VI), and immediate autotransplantation (AT) was performed. Intact PTH (iPTH) levels were measured in the first postoperative week. PTX was classified "total" when iPTH dropped below 10 pg/ml, "subtotal" between 10 and 65 pg/ml, and "insufficient" where levels stayed above 65 pg/ml., Results: According to the postoperative PTH value, tPTX was achieved in 80 of 109 (73.4%) patients (hemodialysis n = 27, normal kidney function: n = 43, restricted: n = 10). PTX was "subtotal" in 25 patients (22.9%), 19 on hemodialysis, 2 had normal, and 4 had restricted kidney graft function. PTX turned out to be insufficient in four patients (3.7%); all of them were on hemodialysis. Insufficient PTX was not observed in kidney-grafted patients. Postoperative temporary laryngeal nerve morbidity was 1.8% (no permanent paresis)., Conclusions: Although applying a very radical concept in patients with RHPT, PTX was "total" in only 73.4%. Persistence of disease was avoided in 91.7%, and low morbidity was documented. In conclusion, it seems difficult to remove all parathyroid tissue from the neck which has to be considered when choosing the surgical procedure.

Published
2018
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13. TP53 is not a prognostic marker-clinical consequences of a generally disregarded fact.

Author

Braunschmid T, Kührer I, Mittlböck M, Westerhoff M, Kappel-Latif S, Brammen L, Krishnadath KK, Phillips WA, Gnant M, and Kandioler D

Subjects
Humans, Prognosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Neoplasms diagnosis, Neoplasms genetics, Neoplasms metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
Abstract

Technological progress within the last 15-20 years has significantly increased our knowledge about the molecular basis of cancer development, tumor progression, and treatment response. As a consequence, a vast number of biomarkers have been proposed, but only a small fraction of them have found their way into clinical use. The aim of this paper is to describe the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. We name this procedure the "triple-R principle": robustness, reproducibility, and relevance. The usefulness of this principle is illustrated with the marker TP53. Since it is mutated in a broad spectrum of cancer entities, TP53 can be considered a very promising marker. Thus, TP53 has been studied in detail but there is still no explicit consensus about its clinical value. By considering our own experience and reviewing the literature, we demonstrate that a major problem of current biomarker research is disregard of whether the biomarker is prognostic or predictive. As an example, it is demonstrated that TP53 is not a prognostic marker, but rather a purely predictive marker, and that disregard of this fact has made this otherwise strong biomarker appear as not being clinically useful so far., (© 2018 New York Academy of Sciences.)

Published
2018
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14. Medullary Thyroid Carcinoma: Do Ultrasonography and F-DOPA-PET-CT Influence the Initial Surgical Strategy?

Author

Brammen L, Niederle MB, Riss P, Scheuba C, Selberherr A, Karanikas G, Bodner G, Koperek O, and Niederle B

Subjects
Adolescent, Adult, Aged, Calcitonin blood, Carcinoma, Neuroendocrine secondary, Child, Clinical Decision-Making, Dihydroxyphenylalanine analogs & derivatives, False Negative Reactions, False Positive Reactions, Female, Humans, Lymphatic Metastasis, Male, Mediastinum, Middle Aged, Neck, Neoplasm Staging, Prospective Studies, Sensitivity and Specificity, Thyroid Neoplasms pathology, Tumor Burden, Young Adult, Carcinoma, Neuroendocrine diagnostic imaging, Carcinoma, Neuroendocrine surgery, Lymph Nodes diagnostic imaging, Positron Emission Tomography Computed Tomography, Thyroid Neoplasms diagnostic imaging, Thyroid Neoplasms surgery, Ultrasonography
Abstract

Background: At the time of diagnosis, one-third of medullary thyroid carcinoma (MTC) patients show lymph node (LN) or distant metastasis. A metastasized MTC requires different surgical strategies., Objective: This study aimed to determine the value of ultrasound and [18F]fluoro-dihydroxyphenylalanine positron emission tomography with computed tomography (F-DOPA-PET-CT) in localizing MTC, as well as LN and distant metastasis., Methods: The study included 50 patients (24 males/26 females) with preoperative ultrasound, F-DOPA-PET-CT, and histologically proven MTC. Imaging results were correlated with both preoperative basal calcitonin (bCt) levels and final histology., Results: Tumors were classified as pT1a:17 (diameter, mean ± standard deviation: 5.8 ± 3.0 mm), pT1b:15 (15.0 ± 3.2 mm), pT2:9 (27.3 ± 7.0 mm), and pT3:9 (38.3 ± 24.2 mm). The median bCt level was 202 pg/mL (lower/upper quartile: 82/1074 pg/mL). Ultrasound was positive for tumor in 45/50 (92%) patients (20.0 ± 16.0 mm) and negative in 5 patients (3.2 ± 2.2 mm). Overall, 43/50 (86%) patients had positive F-DOPA local scans (20.0 ± 16.4 mm), while 7 (14%) patients were negative (7.7 ± 8.1 mm). Lastly, 21/50 (42%) patients had LN metastasis; 8/21 (38%) patients had positive LNs suspected with ultrasound, and 12/21 (57%) patients had positive LNs suspected with F-DOPA. Tumor and LN sensitivity of ultrasound was 92% and 43%, respectively, and 86% and 57% of F-DOPA-PET-CT, respectively. In 3/50 (6%) patients and 3/50 (6%) patients, mediastinal LN metastasis and distant metastasis, respectively, were diagnosed only by F-DOPA-PET-CT., Conclusion: Ultrasound and F-DOPA-PET-CT are sensitive for the localization of MTC but not for the presence and location of LN metastasis (limitations: size/number). Only F-DOPA ensures the diagnosis of distant metastasis and influences the extent of LN surgery. Surgical strategy cannot be predicted based on neither ultrasound nor F-DOPA-PET-CT.

Published
2018
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15. Total thyroidectomy (Tx) versus thionamides (antithyroid drugs) in patients with moderate-to-severe Graves' ophthalmopathy - a 1-year follow-up: study protocol for a randomized controlled trial.

Author

Brammen L, Riss P, Lukas J, Gessl A, Dunkler D, Li S, Leisser A, Rezar-Dreindl S, Eibenberger K, Selberherr A, Scheuba C, and Papp A

Subjects
Antithyroid Agents adverse effects, Austria, Clinical Trials, Phase III as Topic, Graves Ophthalmopathy diagnosis, Graves Ophthalmopathy etiology, Humans, Prospective Studies, Randomized Controlled Trials as Topic, Recurrence, Severity of Illness Index, Time Factors, Treatment Outcome, Antithyroid Agents therapeutic use, Graves Ophthalmopathy therapy, Thyroidectomy adverse effects
Abstract

Background: Graves' disease (GD) is characterized by thyrotoxicosis and goiter and arises through circulating autoantibodies that bind to, and stimulate, the thyroid hormone receptor (TSHR). A temporal relation between the onset of hyperthyroidism and the onset of ophthalmopathy, a common extrathyroidal manifestation, has been demonstrated. Graves' ophthalmopathy (GO) is typically characterized by an inflammation and expansion of the extraocular muscles and an increase in retroorbital fat. There are currently three forms of therapies offered for hyperthyroidism caused by Graves' disease: antithyroid drugs (ATD) (thionamides), radioiodine ablation (RAI) and thyroidectomy (Tx). To date, there is no clear recommendation on the treatment of Graves' disease and GO, mainly due to the individuality of the disease in each patient. The aim of the study is to examine the difference in the outcome of GO in patients with moderate-to-severe GO who receive Tx versus further ATD after suffering their first relapse of GO, or in which GO stays the same following the initial decrease in ATD therapy after 6 months., Methods/design: This prospective randomized clinical trial with observer-blinded analysis will analyze 60 patients with moderate-to-severe GO who receive Tx versus ATD without surgery. Main outcome variables include: muscle index measurements via ultrasound and thyroid antibody levels. Additional outcome variables include: Clinical Activity Score (CAScore), NOSPECS score, superonasal index measurements via ultrasound, and quality of life score., Discussion: This study should allow for better therapeutic choices in patients with moderate-to-severe GO. In addition, it should demonstrate whether the outcome of GO in patients with moderate-to-severe GO is better in those who receive early Tx versus further ATD. Furthermore, this study will aim to establish a standard glucocorticoid scheme before and after Tx in patients with moderate-to-severe EO., Trial Registration: Eudra-CT: 2015-003515-38; Medical University of Vienna Protocol Record 1839/2015. Date of Ethics Committee approval: 19 January 2017. Registered on 27 January 2017.

Published
2018
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16. Applicability of a shortened interpretation model for intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism in an endemic goiter region.

Author

Riss P, Geroldinger A, Selberherr A, Brammen L, Heidtmann J, and Scheuba C

Abstract

Background: In primary hyperparathyroidism (pHPT), quick intraoperative parathyroid hormone monitoring (IOPTH) is performed to predict complete excision of hyperfunctioning tissue and therefore cure. In recent years, efforts have been made to make this prediction more accurate and to shorten the duration of the test, respectively, and therefore reduce waiting and total operating time. The aim of this study was to evaluate the practicability and safety of a time-reduced criterion (decline ≥ 35% after 5 min) in a large cohort of patients., Methods: In an 11-year period, all patients operated for pHPT were analyzed. After preoperative localization studies, hyperfunctioning parathyroid tissue was removed and IOPTH monitoring was performed. Intraoperatively, a decline of ≥50% from baseline 10 min after excision of the gland predicted cure. The performance of an interpretation model, using an earlier PTH level was analyzed retrospectively (decline ≥ 35% from baseline 5 min after excision). Differences in sensitivity, specificity, positive/negative predictive value and accuracy were calculated., Results: According to the inclusion criteria, 1018 patients were analyzed. IOPTH predicted cure in 854 patients (83.9%) 10 min after gland excision with a false positive decline in 13 patients (1.5%). Applying the modified criterion (≥35% decline within 5 min), 814 patients (80%) showed an appropriate decline (false positive in 18 [2.2%]). Overall, multiple gland disease would have been missed in 7 patients. McNemar's test showed a significantly lower sensitivity, specificity and accuracy applying the "35%" criterion., Conclusions: In an endemic goiter region, a criterion, demanding a ≥ 35% decline 5 min after excision can not be recommended for IOPTH monitoring in patients with pHPT., Competing Interests: P. Riss, A. Geroldinger, A. Selberherr, L. Brammen, J. Heidtmann and C. Scheuba declare that they have no competing interests.

Published
2018
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17. A retrospective analysis of the accuracy of radioactively labeled autologous leukocytes in patients with infected prosthetic joints.

Author

Brammen L, Palestro CJ, Holinka J, Windhager R, and Sinzinger H

Subjects
Adult, Aged, Aged, 80 and over, Bone Marrow diagnostic imaging, C-Reactive Protein metabolism, Humans, Isotope Labeling, Leukocyte Count, Middle Aged, Prosthesis-Related Infections metabolism, Radionuclide Imaging, Retrospective Studies, Sensitivity and Specificity, Young Adult, Joint Prosthesis microbiology, Leukocytes metabolism, Prosthesis-Related Infections blood, Prosthesis-Related Infections diagnostic imaging, Technetium Tc 99m Exametazime metabolism
Abstract

Background: Labeled leukocyte scintigraphy (LS) is considered a valuable tool in preoperative diagnosis of prosthetic joint infections (PJI). The aim of this study was to determine the accuracy of LS combined with bone marrow scintigraphy (BMS), as well as inflammation markers CRP and WBC, in detecting infection in patients with prosthetic joints., Material and Methods: This study included patients suspected of having PJI between January and September 2013 at the Vienna General Hospital who underwent imaging with 99mTc-HMPAO labeled autologous leukocytes and subsequent BMS. Diagnostic accuracy was assessed in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)., Results: A total of 48 patients were included. The most common joint investigated was knee (25), followed by hip (9), shoulder (2), and elbow (1). Other parts of the body investigated included the femur (6), tibia (2), leg (2), and foot (1). The pathogens most frequently isolated included Staphylococcus epidermidis and Candida albicans. The sensitivity of LS was 60%, specificity 97%, PPV 86% and NPV 90%. Overall accuracy was calculated to be 90%., Conclusions: This study was able to demonstrate that 99mTc-HMPAO labeled autologous leukocytes in patients presenting with symptoms of PJI is accurate. In contrast, however, inflammation markers CRP and WBC are not accurate pre-diagnostic markers for PJI.

Published
2017
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18. The effect of elevated lipoprotein(a) on autologous platelets function: a retrospective analysis.

Author

Brammen L, Granegger S, and Sinzinger H

Subjects
Adult, Cells, Cultured, Humans, Indium, Male, Metabolic Clearance Rate, Middle Aged, Up-Regulation physiology, Blood Platelets metabolism, Isotope Labeling methods, Lipoprotein(a) metabolism, Platelet Transfusion methods, Radiopharmaceuticals pharmacokinetics
Abstract

Objective: Platelet labeling is used to study platelets in vivo in terms of diagnosing intravascular thrombosis, as well as studying their role and biological activity in atherosclerosis. A low labeling efficiency (LE) can negatively impair testing results. Labeling efficiency depends on various factors, including low-density-lipoprotein (LDL)-cholesterol levels in the blood. Lipoprotein(a) (Lp(a)) is a lipoprotein subclass that when elevated, is frequently associated with the premature development of cardiovascular disease through activation of different signaling pathways and cell surface receptors., Subjects and Methods: We retrospectively studied 51 patients with isolated elevated Lp(a) (>50 mg/dL, ranging up to 440 mg/dL) compared to patients with normal lipid profiles who underwent autologous radioactive platelet labeling during the time period of January 2001-September 2013 at the Vienna General Hospital. Platelets were radiolabeled according to ISORBE consensus., Results: LE was decreased in patients with elevated Lp(a). Cross-incubation of hyper-Lp(a) patients with normal Lp(a) plasma and vice versa demonstrated that platelets themselves and not the plasmatic environment are accountable for the decline in LE. Furthermore, LE positively correlated with an increase in platelet incubation time, the highest LE being seen after 30 minutes., Conclusion: This study determined that extremely elevated Lp(a) profiles, especially values greater than 150 mg/dL, may significantly impair platelets function such as labeling results. Platelets are responsible for the decrease in LE in hyper-Lp(a) patients. Non-HDL-Lp is the most informative parameter of impaired LE. We thus recommend to include Lp(a) in the list of parameters that need to be taken into consideration in studying autologous radiolabeled platelets.

Published
2016
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19. Molecular imaging of atherosclerotic lesions by positron emission tomography - can it meet the expectations?

Author

Brammen L, Steiner S, Berent R, and Sinzinger H

Subjects
Animals, Atherosclerosis therapy, Disease Models, Animal, Fluorodeoxyglucose F18, Humans, Plaque, Atherosclerotic, Predictive Value of Tests, Prognosis, Radiopharmaceuticals, Reproducibility of Results, Severity of Illness Index, Sodium Fluoride, Arteries diagnostic imaging, Atherosclerosis diagnostic imaging, Molecular Imaging methods, Positron-Emission Tomography
Abstract

Early non-invasive imaging of atherosclerosis and in particular the detection of lesions at risk with high specificity could significantly affect cardiovascular morbidity and mortality. Conventional nuclear medicine approaches, in particular using autologous radiolabeled lipoproteins, can be related to histopathological findings; however, they fail to identify lesions at risk. Positron emission tomography (PET) tracers with much better physical properties have been examined, the most detailed information being available for F-18-deoxyglucose (FDG) and F-18-sodium fluoride (NaF). These two approaches are sensitive to different biochemical mechanisms, i.e. inflammation and microcalcification. Initial enthusiasm, in particular for F-18-FDG, has disappeared, although for F-18-NaF there is some hope, but this is not a breakthrough. No tracer is available so far that is able to identify a specific characteristic of a lesion prone to rupture. Other PET tracers in the pipeline have been examined, mainly in experimental models and only a few in patients, but they failed to contribute significantly to early lesion discovery and do not support great expectations. The key question is: Do we understand what we see? Moreover, methodological problems, a lack of standardization of imaging protocols and aspects of quantification provide a wide range for potential future improvements. While monitoring a therapeutic intervention seems to be possible for both F-18-FDG and F-18-NaF, highly specific early identification of lesions at risk by PET imaging is still far away. As of today, PET is not ready for routine clinical judgment of atherosclerotic lesions at risk to rupture. Even if all these problems can be solved, radiation exposure will still remain a concern, in particular for repeated studies.

Published
2016
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20. Radionuclide imaging: Past, present and future outlook in the diagnosis of infected prosthetic joints.

Author

Brammen L, Palestro C, and Sinzinger H

Abstract

Objective: A serious complication of joint replacement surgery is infection, which results in prolonged invalidity as well as removal and subsequent re-implantation after lengthy antibiotic therapy. In terms of diagnostic imaging, nuclear medicine has presented several tracers and imaging modalities over the years to be used in prosthetic joint infection. The PubMed/MEDLINE literature database was systematically examined for publications on infection, arthroplasty, joint replacement, prosthetic joint, gallium, labeled leukocytes, sulfur colloid, antimicrobial peptides, Fluorine-18-fluorodeoxyglucose ((18)F-FDG), positron emission tomography/computed tomography (PET-CT), and single-photon emission (SPET-CT). This was determined to be a comprehensive review, not a meta-analysis of prosthetic joint infection and diagnostic imaging in the field of nuclear medicine. Prosthetic joint replacement is more frequently being employed as a way of improving the quality of life in an ever-ageing population. Complications following joint replacement surgery include aseptic or mechanical loosening, as well as polyethylene wear and prosthetic joint infection. The rate of infection is estimated to be between 1%-3%. The therapeutic management of these complications lies in the ability to differentiate between infection and aseptic mechanical loosening. Given that plain radiographs are neither sensitive nor specific to infection and computer tomography, as well as magnetic resonance imaging are limited due to metal-induced artifacts, radionuclide imaging has come to aid in the diagnostic imaging in the failed joint replacement. However, each modality has its advantages and disadvantages, thus there is no gold standard technique of radionuclide imaging. Nevertheless, radiolabelled leukocyte scintigraphy has proven itself to be the gold standard in neutrophil-based infection processes. Several studies have examined the role of PET using radiotracers such as (18)F-FDG, gallium-67 and (18)F, as well as SPET-CT in diagnosing prosthetic joint infections. Other radiotracers, such as antigranulocyte antibodies and fragments, as well as radiolabeled antibodies and antimicrobial peptide have yet to confirm their role in diagnostic imaging of the failed joint replacement. Nuclear medicine plays a vital role in diagnosing prosthetic joint infections. WBC/bone marrow imaging is the best available diagnostic imaging test. Newer imaging modalities, such as SPET-CT may in the future, play a larger role in diagnosing prosthetic joint infections. The roles of (18)F-PET and (18)F-FDG-PET have yet to still be determined.

Published
2015

21. Extraordinary Lymph Drainage in Cutaneous Malignant Melanoma and the Value of Hybrid Imaging: A Case Report.

Author

Brammen L, Nedomansky J, Haslik W, and Staudenherz A

Abstract

In melanoma patients, preoperative lymphoscintigraphy has become a gold standard. The role of single-photon emission computed tomography (SPECT) or its combination with computed tomography (SPECT-CT) as part of the standard sentinel scintigraphy protocol has yet to be determined. A 46-year-old female patient with melanoma of the trunk received preoperative lymphoscintigraphy and subsequent surgical excision. Planar imaging displayed two hot spots in the region of the primary lesion. No other lymphatic flow pathways could be appreciated. Two focal hot spots, one dorsal to the primary lesion near the left latissimus dorsi muscle and one just lateral to the primary lesion in the subcutaneous tissue, were appreciated with SPECT-CT imaging. The primary melanoma lesion, as well as the two additional lesions, which were detected by SPECT-CT, were excised and sent for histopathological examination. While the primary lesion was a superficial spreading melanoma, the lesions appreciated in SPECT-CT revealed four sentinel lymph nodes, each of which was negative for tumor cells. Melanomas, especially of the trunk, can demonstrate multiple lymphatic drain basins in a large percentage of patients. Given that without the detailed anatomical information provided by SPECT-CT it would be very difficult to locate the diverse lymphatic drain basins and their lymph nodes, we would suggest routinely implementing SPECT-CT in the standard planar sentinel imaging protocol.

Published
2014
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22. Sentinel lymph node detection in vulvar cancer patients: a 20 years analysis.

Author

Brammen L, Staudenherz A, Polterauer S, Dolliner P, Grimm C, Reinthaller A, and Sinzinger H

Subjects
Aged, Female, Humans, Longitudinal Studies, Lymphatic Metastasis, Reproducibility of Results, Risk Assessment methods, Sensitivity and Specificity, Sentinel Lymph Node Biopsy methods, Treatment Outcome, Lymph Nodes diagnostic imaging, Lymph Nodes surgery, Neoplasm Recurrence, Local diagnostic imaging, Neoplasm Recurrence, Local prevention & control, Radionuclide Imaging methods, Vulvar Neoplasms diagnostic imaging, Vulvar Neoplasms surgery
Abstract

Our study aimed to analyze postoperative treatment-related morbidity after sentinel lymph node biopsy (SLNB) compared to systematic inguinofemoral lymph node dissection (ILND) and the recurrence rate in patients with vulvar cancer. This single center study included 128 patients diagnosed with vulvar cancer that underwent ILND or SLNB between January 1991 - January 2011 with intraoperative SLN detection and removal. Treatment-related morbidity, as well as recurrence rate of SLNB patients were evaluated. Preoperative sentinel node scintigraphy was successful in 82/89 (92%) of the patients. A hundred and seventy six nodes were visualized and all positive SLN were detected within 60min. Patients who were treated with ILND underwent a longer operation (P<0.001), required longer inguinal drainage (P<0.001), and had a lengthier postoperative hospital stay (P=0.006). The presence of lymph cysts (P=0.02, 95% CI 3.4 (1-1-10.6) was significantly higher in ILND patients. No groin recurrence was appreciated in SLNB patients. In conclusion, patients who underwent SLNB were at a lower risk of postoperative morbidity. No groin recurrences were observed in patients who received SLNB.

Published
2014
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23. Impact of conization type on the resected cone volume: results of a retrospective multi-center study.

Author

Grimm C, Brammen L, Sliutz G, Weigert M, Sevelda P, Pils S, Reinthaller A, and Polterauer S

Subjects
Adult, Age Factors, Cervix Uteri pathology, Female, Humans, Middle Aged, Retrospective Studies, Secondary Care Centers, Tertiary Care Centers, Uterine Cervical Neoplasms pathology, Uterine Cervical Dysplasia pathology, Cervix Uteri surgery, Conization methods, Uterine Cervical Neoplasms surgery, Uterine Cervical Dysplasia surgery
Abstract

Purpose: The extent of conization seems to influence the risk of preterm birth. The aim of this study was to compare the cone volume after surgical resection with large loop excision of the transformation zone (LLETZ) and cold knife conization (CKC)., Methods: The present retrospective multi-center study comprises 804 consecutive women, who underwent LLETZ (n = 412) or CKC (n = 392) between 2004 and 2009. Univariate and multivariable analyses were performed to compare cone volumes removed by LLETZ and CKC and identify independent risk factors for large cone volume., Results: The median resected cone volume after LLETZ was significantly smaller [1.6 cm(3) (0.8-2.9)] than after CKC [2.1 cm(3) (1.4-3.5)] (<0.0001). Complete resection rates were comparable in both groups. Conization method, cone depth, and institution type were independent risk factors for removal of a large cone volume., Conclusion: CKC removes larger cone volumes than LLETZ without the advantage of higher complete resection rates.

Published
2013
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24. Portable recording for detecting sleep disorder breathing in patients under the care of a heart failure clinic.

Author

Dolliner P, Brammen L, Graf S, Huelsmann M, Stiebellehner L, Gleiss A, Ubl P, and Steurer G

Subjects
Adult, Aged, Aged, 80 and over, Disorders of Excessive Somnolence diagnosis, Female, Heart Failure therapy, Humans, Male, Middle Aged, Natriuretic Peptide, Brain metabolism, Peptide Fragments metabolism, Prevalence, Prospective Studies, Severity of Illness Index, Sleep Apnea Syndromes diagnosis, Sleep Apnea Syndromes epidemiology, Sleep Apnea, Central diagnosis, Sleep Apnea, Obstructive diagnosis, Ventricular Function, Left, Disorders of Excessive Somnolence epidemiology, Heart Failure physiopathology, Sleep Apnea, Central epidemiology, Sleep Apnea, Obstructive epidemiology
Abstract

Background: Sleep disordered breathing (SDB) has important clinical implications in patients with congestive heart failure (CHF). We performed portable recording in unselected CHF patients on contemporary therapy. Data on the interactions of SDB in patients supervised at heart failure clinics are rare and we illustrate diversities of obstructive sleep apnoea (OSA) and central sleep apnoea (CSA)., Methods: We studied 176 consecutive subjects on contemporary medical therapy with a median left ventricular ejection fraction of 25.0 % (range 7-35%) and median NT-pro BNP levels of 3,413.0 pg/ml (range 305.1-35,000.0 pg/ml). Participants underwent prospective overnight portable recording., Results: 50% presented with an at least moderate form of nocturnal breathing disorder [apnoea-hypopnoea index (AHI) ≥15/h]. Only 15 patients (17.1%) with AHI ≥15/h reported excessive daytime sleepiness. Irrespective of left ventricular ejection fraction, patients with CSA had higher levels of NT-pro BNP compared to patients with OSA (differences in medians = 2,639.0 pg/ml, p = 0.016), and compared to patients with an AHI <15/h (differences in medians = 2,710.0 pg/ml, p < 0.001). OSA affected 26 patients (14.8%)., Conclusions: Patients with severe stable CHF on contemporary therapy have a prevalence of 50.0% of moderate to severe SDB. The natural cascade of the failing heart is initially characterised by absent SDB or OSA, whereas end-stage CHF is associated with CSA.

Published
2013
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