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1. Treatment and survival of locally recurrent rectal cancer: A cross-sectional population study 15 years after the Dutch TME trial

Author

Aalbers, A.G.J., Acherman, Y., Algie, G.D., Alting von Geusau, B., Amelung, F., Aukema, T.S., Bakker, I.S., Bartels, S.A., Basha, S., Bastiaansen, A.J.N.M., Belgers, E., Bleeker, W., Blok, J., Bosker, R.J.I., Bosmans, J.W., Boute, M.C., Bouvy, N.D., Bouwman, H., Brandt-Kerkhof, A., Brinkman, D.J., Bruin, S., Bruns, E.R.J., Burbach, J.P.M., Burger, J.W.A., Buskens, C.J., Clermonts, S., Coene, P.P.L.O., Compaan, C., Consten, E.C.J., Darbyshire, T., de Mik, S.M.L., de Graaf, E.J.R., de Groot, I., tot Nederveen Cappel, RJ de Vos, de Wilt, J.H.W., van der Wolde, J., Boer, FC den, Dekker, J.W.T., Demirkiran, A., Derkx-Hendriksen, M., Dijkstra, F.R., van Duijvendijk, P., Dunker, M.S., Eijsbouts, Q.E., Fabry, H., Ferenschild, F., Foppen, J.W., Furnee, E.J.B., Gerhards, M.F., Gerven, P., Gooszen, J.A.H., Govaert, J.A., Van Grevenstein, W.M.U., Haen, R., Harlaar, J.J., van der Harst, E., Havenga, K., Heemskerk, J., Heeren, J.F., Heijnen, B., Heres, P., Hoff, C., Hogendoorn, W., Hoogland, P., Huijbers, A., Janssen, P., Jongen, A.C., Jonker, F.H., Karthaus, E.G., Keijzer, A., Ketel, J.M.A., Klaase, J., Kloppenberg, F.W.H., Kool, M.E., Kortekaas, R., Kruyt, P.M., Kuiper, J.T., Lamme, B., Lange, J.F., Lettinga, T., Lips, D.J., Logeman, F., Lutke Holzik, M.F., Madsen, E., Mamound, A., Marres, C.C., Masselink, I., Meerdink, M., Menon, A.G., Mieog, J.S., Mierlo, D., Musters, G.D., Nieuwenhuijzen, G.A.P., Neijenhuis, P.A., Nonner, J., Oostdijk, M., Oosterling, S.J., Paul, P.M.P., Peeters, K.C.M.J., Pereboom, I.T.A., Polat, F., Poortman, P., Raber, M., Reiber, B.M.M., Renger, R.J., van Rossem, C.C., Rutten, H.J., Rutten, A., Schaapman, R., Scheer, M., Schoonderwoerd, L., Schouten, N., Schreuder, A.M., Schreurs, W.H., Simkens, G.A., Slooter, G.D., Sluijmer, H.C.E., Smakman, N., Smeenk, R., Snijders, H.S., Sonneveld, D.J.A., Spaansen, B., Bilgen, EJ Spillenaar, Steller, E., Steup, W.H., Steur, C., Stortelder, E., Straatman, J., Swank, H.A., Sietses, C., Groen, H.A., Hoeve, HG ten, Riele, WW ter, Thorensen, I.M., Tip-Pluijm, B., Toorenvliet, B.R., Tseng, L., Tuynman, J.B., van Bastelaar, J., van Beek, S.C., van de Ven, A.W.H., van de Weijer, M.A.J., van den Berg, C., van den Bosch, I., van der Bilt, J.D.W., van der Hagen, S.J., van der Hul, R., van der Schelling, G., van der Spek, A., van der Wielen, N., van Duyn, E., van Eekelen, C., van Essen, J.A., van Gangelt, K., van Geloven, A.A.W., van Kessel, C., van Loon, Y.T., van Rijswijk, A., van Rooijen, S.J., van Sprundel, T., van Steensel, L., van Tets, W.F., van Westreenen, H.L., Veltkamp, S., Verhaak, T., Verheijen, P.M., Versluis-Ossenwaarde, L., Vijfhuize, S., Vles, W.J., Voeten, S.C., Vogelaar, F.J., Vrijland, W.W., Westerduin, E., Westerterp, M.E., Wetzel, M., Wevers, K.P., Wiering, B., Witjes, C.D.M., Wouters, M.W., Yauw, S.T.K., van der Zaag, E.S., Zeestraten, E.C., Zimmerman, D.D.E., Zwieten, T., Detering, Robin, Karthaus, Eleonora G., Borstlap, Wernard A.A., Marijnen, Corrie A.M., van de Velde, Cornelis J.H., Bemelman, Willem A., Beets, Geerard L., Tanis, Pieter J., and Aalbers, Arend G.J.

Published
2019
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2. The influence of hospital volume on long-term oncological outcome after rectal cancer surgery

Author

Jonker, Frederik H. W., Hagemans, Jan A. W., Burger, Jacobus W. A., Verhoef, Cornelis, Borstlap, Wernard A. A., Tanis, Pieter J., Aalbers, A., Acherman, Y., Algie, G. D., Alting von Geusau, B., Amelung, F., Aukema, T. S., Bakker, I. S., Bartels, S. A., Basha, S., Bastiaansen, A. J. N. M., Belgers, E., Bemelman, W. A., Bleeker, W., Blok, J., Bosker, R. J. I., Bosmans, J. W., Boute, M. C., Bouvy, N. D., Bouwman, H., Brandt-Kerkhof, A., Brinkman, D. J., Bruin, S., Bruns, E. R. J., Burbach, J. P. M., Clermonts, S., Coene, P. P. L. O., Compaan, C., Consten, E. C. J., Darbyshire, T., de Mik, S. M. L., de Graaf, E. J. R., de Groot, I., de vos tot Nederveen Cappel, R. J. L., de Wilt, J. H. W., van der Wolde, J., den Boer, F. C., Dekker, J. W. T., Demirkiran, A., Derkx-Hendriksen, M., Dijkstra, F. R., van Duijvendijk, P., Dunker, M. S., Eijsbouts, Q. E., Fabry, H., Ferenschild, F., Foppen, J. W., Furnée, E. J. B., Gerhards, M. F., Gerven, P., Gooszen, J. A. H., Govaert, J. A., Van Grevenstein, W. M. U., Haen, R., Harlaar, J. J., Harst, E., Havenga, K., Heemskerk, J., Heeren, J. F., Heijnen, B., Heres, P., Hoff, C., Hogendoorn, W., Hoogland, P., Huijbers, A., Gooszen, J. A. H., Janssen, P., Jongen, A. C., Karthaus, E. G., Keijzer, A., Ketel, J. M. A., Klaase, J., Kloppenberg, F. W. H., Kool, M. E., Kortekaas, R., Kruyt, P. M., Kuiper, J. T., Lamme, B., Lange, J. F., Lettinga, T., Lips, D. J., Logeman, F., Lutke Holzik, M. F., Madsen, E., Mamound, A., Marres, C. C., Masselink, I., Meerdink, M., Menon, A. G., Mieog, J. S., Mierlo, D., Musters, G. D., Neijenhuis, P. A., Nonner, J., Oostdijk, M., Oosterling, S. J., Paul, P. M. P., Peeters, K. C. M. J. C., Pereboom, I. T. A., Polat, F., Poortman, P., Raber, M., Reiber, B. M. M., Renger, R. J., van Rossem, C. C., Rutten, H. J., Rutten, A., Schaapman, R., Scheer, M., Schoonderwoerd, L., Schouten, N., Schreuder, A. M., Schreurs, W. H., Simkens, G. A., Slooter, G. D., Sluijmer, H. C. E., Smakman, N., Smeenk, R., Snijders, H. S., Sonneveld, D. J. A., Spaansen, B., Spillenaar Bilgen, E. J., Steller, E., Steup, W. H., Steur, C., Stortelder, E., Straatman, J., Swank, H. A., Sietses, C., ten Berge, H. A., ten hoeve, H. G., ter Riele, W. W., Thorensen, I. M., Tip-Pluijm, B., Toorenvliet, B. R., Tseng, L., Tuynman, J. B., van Bastelaar, J., van beek, S. C., van de Ven, A. W. H., van de Weijer, M. A. J., van den Berg, C., van den Bosch, I., van der Bilt, J. D. W., van der Hagen, S. J., van der hul, R., van der Schelling, G., van der Spek, A., van der Wielen, N., van duyn, E., van Eekelen, C., van Essen, J. A., van Gangelt, K., van Geloven, A. A. W., van kessel, C., van Loon, Y. T., van Rijswijk, A., van Rooijen, S. J., van Sprundel, T., van Steensel, L., van Tets, W. F., van Westreenen, H. L., Veltkamp, S., Verhaak, T., Verheijen, P. M., Versluis-Ossenwaarde, L., Vijfhuize, S., Vles, W. J., Voeten, S., Vogelaar, F. J., Vrijland, W. W., Westerduin, E., Westerterp, M. E., Wetzel, M., Wevers, K., Wiering, B., Witjes, A. C., Wouters, M. W., Yauw, S. T. K., Zeestraten, E. C., Zimmerman, D. D., Zwieten, T., and Dutch Snapshot Research Group

Published
2017
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3. Tussen vinding en conventie. Een onderzoek naar de artistieke praktijk van Jan Stolker (1724-1785) en het achttiende-eeuwse concept van originaliteit

Author

Steur, C., Hoogenboom, A.M.E.L. (Thesis Advisor), Stolwijk, C.W.M., Steur, C., Hoogenboom, A.M.E.L. (Thesis Advisor), and Stolwijk, C.W.M.

Abstract

Doorheen de tijd zijn Jan Stolkers (1724-1785) kopieën en imitaties op verschillende manieren benaderd door kunsthistorici. In de eerste helft van de twintigste eeuw heeft de nadruk op originaliteit onder modernistische kunsthistorici bijgedragen aan een negatief oordeel over Stolker en zijn kopiërende werkwijze. Zijn toepassing van kopieermethoden werd in de vroegmoderne tijd echter nog beschouwd als een onderdeel van het artistieke proces. Deze masterscriptie onderzoekt hoe de artistieke praktijk van Stolker zich verhoudt tot het achttiende-eeuwse concept van originaliteit. Hierbij is het verloop van het kunsthistorische debat over originaliteit en aanverwante begrippen als uitgangspunt genomen. Er blijken veel verschillende gradaties te zijn in de manier waarop een kopie of imitatie zich tot het origineel verhoudt. Deze variatie is ook terug te zien in de drie casestudies die gewijd zijn aan de thema’s die door Stolker het meest intensief nagevolgd zijn. In zijn historiserende portretten heeft Stolker bestaande portretten nagebootst in een zelfbedachte compositie, terwijl hij in zijn werken naar zeventiende-eeuwse meesters de voorstellingen in hun geheel heeft overgenomen. Zijn werk naar Jacob de Wit (1695-1754) toont weer het hergebruik van losse motieven. Als drijfveren voor de populariteit van kopieën en imitaties in de achttiende eeuw zijn in recente kunsthistorische onderzoeken een groeiend nationaal besef en de smaak van kunstverzamelaars aangedragen. In deze scriptie is voortgebouwd op het vermoeden dat Stolker als onderdeel van deze verzamelcultuur met zijn imitaties actief uitdrukking gaf aan zijn eigen historische belangstelling en geleerdheid. De door hem toegepaste kopieertechnieken in zijn tekeningen geven inzicht in zijn creatieve ontwerpproces. Een unieke collectie lijntekeningen van Stolker uit Museum Boijmans Van Beuningen toont de sporen van deze technische toepassing en vormt de rode draad in de casestudies. Om een zo volledig mogelijk beeld va

Published
2020

4. Treatment and survival of locally recurrent rectal cancer: A cross-sectional population study 15 years after the Dutch TME trial

Author

Detering, Robin, primary, Karthaus, Eleonora G., additional, Borstlap, Wernard A.A., additional, Marijnen, Corrie A.M., additional, van de Velde, Cornelis J.H., additional, Bemelman, Willem A., additional, Beets, Geerard L., additional, Tanis, Pieter J., additional, Aalbers, Arend G.J., additional, Aalbers, A.G.J., additional, Acherman, Y., additional, Algie, G.D., additional, Alting von Geusau, B., additional, Amelung, F., additional, Aukema, T.S., additional, Bakker, I.S., additional, Bartels, S.A., additional, Basha, S., additional, Bastiaansen, A.J.N.M., additional, Belgers, E., additional, Bleeker, W., additional, Blok, J., additional, Bosker, R.J.I., additional, Bosmans, J.W., additional, Boute, M.C., additional, Bouvy, N.D., additional, Bouwman, H., additional, Brandt-Kerkhof, A., additional, Brinkman, D.J., additional, Bruin, S., additional, Bruns, E.R.J., additional, Burbach, J.P.M., additional, Burger, J.W.A., additional, Buskens, C.J., additional, Clermonts, S., additional, Coene, P.P.L.O., additional, Compaan, C., additional, Consten, E.C.J., additional, Darbyshire, T., additional, de Mik, S.M.L., additional, de Graaf, E.J.R., additional, de Groot, I., additional, tot Nederveen Cappel, RJ de Vos, additional, de Wilt, J.H.W., additional, van der Wolde, J., additional, Boer, FC den, additional, Dekker, J.W.T., additional, Demirkiran, A., additional, Derkx-Hendriksen, M., additional, Dijkstra, F.R., additional, van Duijvendijk, P., additional, Dunker, M.S., additional, Eijsbouts, Q.E., additional, Fabry, H., additional, Ferenschild, F., additional, Foppen, J.W., additional, Furnee, E.J.B., additional, Gerhards, M.F., additional, Gerven, P., additional, Gooszen, J.A.H., additional, Govaert, J.A., additional, Van Grevenstein, W.M.U., additional, Haen, R., additional, Harlaar, J.J., additional, van der Harst, E., additional, Havenga, K., additional, Heemskerk, J., additional, Heeren, J.F., additional, Heijnen, B., additional, Heres, P., additional, Hoff, C., additional, Hogendoorn, W., additional, Hoogland, P., additional, Huijbers, A., additional, Janssen, P., additional, Jongen, A.C., additional, Jonker, F.H., additional, Karthaus, E.G., additional, Keijzer, A., additional, Ketel, J.M.A., additional, Klaase, J., additional, Kloppenberg, F.W.H., additional, Kool, M.E., additional, Kortekaas, R., additional, Kruyt, P.M., additional, Kuiper, J.T., additional, Lamme, B., additional, Lange, J.F., additional, Lettinga, T., additional, Lips, D.J., additional, Logeman, F., additional, Lutke Holzik, M.F., additional, Madsen, E., additional, Mamound, A., additional, Marres, C.C., additional, Masselink, I., additional, Meerdink, M., additional, Menon, A.G., additional, Mieog, J.S., additional, Mierlo, D., additional, Musters, G.D., additional, Nieuwenhuijzen, G.A.P., additional, Neijenhuis, P.A., additional, Nonner, J., additional, Oostdijk, M., additional, Oosterling, S.J., additional, Paul, P.M.P., additional, Peeters, K.C.M.J., additional, Pereboom, I.T.A., additional, Polat, F., additional, Poortman, P., additional, Raber, M., additional, Reiber, B.M.M., additional, Renger, R.J., additional, van Rossem, C.C., additional, Rutten, H.J., additional, Rutten, A., additional, Schaapman, R., additional, Scheer, M., additional, Schoonderwoerd, L., additional, Schouten, N., additional, Schreuder, A.M., additional, Schreurs, W.H., additional, Simkens, G.A., additional, Slooter, G.D., additional, Sluijmer, H.C.E., additional, Smakman, N., additional, Smeenk, R., additional, Snijders, H.S., additional, Sonneveld, D.J.A., additional, Spaansen, B., additional, Bilgen, EJ Spillenaar, additional, Steller, E., additional, Steup, W.H., additional, Steur, C., additional, Stortelder, E., additional, Straatman, J., additional, Swank, H.A., additional, Sietses, C., additional, Groen, H.A., additional, Hoeve, HG ten, additional, Riele, WW ter, additional, Thorensen, I.M., additional, Tip-Pluijm, B., additional, Toorenvliet, B.R., additional, Tseng, L., additional, Tuynman, J.B., additional, van Bastelaar, J., additional, van Beek, S.C., additional, van de Ven, A.W.H., additional, van de Weijer, M.A.J., additional, van den Berg, C., additional, van den Bosch, I., additional, van der Bilt, J.D.W., additional, van der Hagen, S.J., additional, van der Hul, R., additional, van der Schelling, G., additional, van der Spek, A., additional, van der Wielen, N., additional, van Duyn, E., additional, van Eekelen, C., additional, van Essen, J.A., additional, van Gangelt, K., additional, van Geloven, A.A.W., additional, van Kessel, C., additional, van Loon, Y.T., additional, van Rijswijk, A., additional, van Rooijen, S.J., additional, van Sprundel, T., additional, van Steensel, L., additional, van Tets, W.F., additional, van Westreenen, H.L., additional, Veltkamp, S., additional, Verhaak, T., additional, Verheijen, P.M., additional, Versluis-Ossenwaarde, L., additional, Vijfhuize, S., additional, Vles, W.J., additional, Voeten, S.C., additional, Vogelaar, F.J., additional, Vrijland, W.W., additional, Westerduin, E., additional, Westerterp, M.E., additional, Wetzel, M., additional, Wevers, K.P., additional, Wiering, B., additional, Witjes, C.D.M., additional, Wouters, M.W., additional, Yauw, S.T.K., additional, van der Zaag, E.S., additional, Zeestraten, E.C., additional, Zimmerman, D.D.E., additional, and Zwieten, T., additional

Published
2019
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5. Influence of Conversion and Anastomotic Leakage on Survival in Rectal Cancer Surgery; Retrospective Cross-sectional Study

Author

Furnee, E.J.B., Aukema, T.S., Oosterling, S.J., Borstlap, W.A.A., Bemelman, W.A., Tanis, P.J., Aalbers, A., Acherman, Y., Algie, G.D., Geusau, B.A. von, Amelung, F., Bartels, S.A., Basha, S., Bastiaansen, A.J.N.M., Belgers, E., Bleeker, W., Blok, J., Bosker, R.J.I., Bosmans, J.W., Boute, M.C., Bouvy, N.D., Bouwman, H., Brandt-Kerkhof, A., Brinkman, D.J., Bruin, S., Bruns, E.R.J., Burbach, J.P.M., Burger, J.W.A., Buskens, C.J., Clermonts, S., Coene, P.P.L.O., Compaan, C., Consten, E.C.J., Darbyshire, T., Mik, S.M.L. de, Graaf, E.J.R. de, Groot, I. de, Cappel, R.J.L.D.N., Wilt, J.H.W. de, Wolde, J. van der, Boer, F.C. den, Dekker, J.W.T., Demirkiran, A., Derkx-Hendriksen, M., Dijkstra, F.R., Duijvendijk, P. van, Dunker, M.S., Eijsbouts, Q.E., Fabry, H., Ferenschild, F., Foppen, J.W., Gerhards, M.F., Gerven, P., Gooszen, J.A.H., Govaert, J.A., Grevenstein, W.M.U. van, Haen, R., Harlaar, J.J., Harst, E., Havenga, K., Heemskerk, J., Heeren, J.F., Heijnen, B., Heres, P., Hoff, C., Hogendoorn, W., Hoogland, P., Huijbers, A., Janssen, P., Jongen, A.C., Jonker, F.H., Karthaus, E.G., Keijzer, A., Ketel, J.M.A., Klaase, J., Kloppenberg, F.W.H., Kool, M.E., Kortekaas, R., Kruyt, P.M., Kuiper, J.T., Lamme, B., Lange, J.F., Lettinga, T., Lips, D.J., Logeman, F., Holzik, M.F.L., Madsen, E., Mamound, A., Marres, C.C., Masselink, I., Meerdink, M., Menon, A.G., Mieog, J.S., Mierlo, D., Musters, G.D., Nieuwenhuijzen, G.A.P., Neijenhuis, P.A., Nonner, J., Oostdijk, M., Paul, P.M.P., Peeters, K.C.M.J., Pereboom, I.T.A., Polat, F., Poortman, P., Raber, M., Reiber, B.M.M., Renger, R.J., Rossem, C.C. van, Rutten, H.J., Rutten, A., Schaapman, R., Scheer, M., Schoonderwoerd, L., Schouten, N., Schreuder, A.M., Schreurs, W.H., Simkens, G.A., Slooter, G.D., Sluijmer, H.C.E., Smakman, N., Smeenk, R., Snijders, H.S., Sonneveld, D.J.A., Spaansen, B., Bilgen, E.J.S., Steller, E., Steup, W.H., Steur, C., Stortelder, E., Straatman, J., Swank, H.A., Sietses, C., Berge, H.A. ten, Hoeve, H.G. ten, Riele, W.W. ter, Thorensen, I.M., Tip-Pluijm, B., Toorenvliet, B.R., Tseng, L., Tuynman, J.B., Bastelaar, J. van, Beek, S.C. van, Ven, A.W.H. van de, Weijer, M.A.J. van de, Berg, C. van den, Bosch, I. van den, Bilt, J.D.W. van der, Hagen, S.J. van der, Hul, R. van der, Schelling, G. van der, Spek, A. van der, Wielen, N. van der, Duyn, E. van, Eekelen, C. van, Essen, J.A. van, Gangelt, K. van, Geloven, A.A.W. van, Kessel, C. van, Loon, Y.T. van, Rijswijk, A. van, Rooijen, S.J. van, Sprundel, T. van, Steensel, L. van, Tets, W.F. van, Westreenen, H.L. van, Veltkamp, S., Verhaak, T., Verheijen, P.M., Versluis-Ossenwaarde, L., Vijfhuize, S., Vles, W.J., Voeten, S., Vogelaar, F.J., Vrijland, W.W., Westerduin, E., Westerterp, M.E., Wetzel, M., Wevers, K.P., Wiering, B., Witjes, C.D.M., Wouters, M.W., Yauw, S.T.K., Zaag, E.S. van der, Zeestraten, E.C., Zimmerman, D.D., Zwieten, T., and Dutch Snapshot Res Grp

Subjects
Survival, Anastomosis, Laparoscopy, Conversion, Rectal cancer
Published
2019

6. Cross-Sectional Study on MRI Restaging After Chemoradiotherapy and Interval to Surgery in Rectal Cancer: Influence on Short- and Long-Term Outcomes

Author

Detering, R., Borstlap, W.A.A., Broeders, L., Hermus, L., Marijnen, C.A.M., Beets-Tan, R.G.H., Bemelman, W.A., Westreenen, H.L. van, Tanis, P.J., Aalbers, A., Acherman, Y., Algie, G.D., Geusau, B.A. von, Amelung, F., Bartels, S.A., Basha, S., Bastiaansen, A.J.N.M., Belgers, E., Bleeker, W., Blok, J., Bosker, R.J.I., Bosmans, J.W., Boute, M.C., Bouvy, N.D., Bouwman, H., Brandt-Kerkhof, A., Brinkman, D.J., Bruin, S., Bruns, E.R.J., Burbach, J.P.M., Burger, J.W.A., Buskens, C.J., Clermonts, S., Coene, P.P.L.O., Compaan, C., Consten, E.C.J., Darbyshire, T., Mik, S.M.L. de, Graaf, E.J.R. de, Groot, I. de, Cappel, R.J.L.D.T.N., Wilt, J.H.W. de, Wolde, J. van der, Boer, F.C. den, Dekker, J.W.T., Demirkiran, A., Derkx-Hendriksen, M., Dijkstra, F.R., Duijvendijk, P. van, Dunker, M.S., Eijsbouts, Q.E., Fabry, H., Ferenschild, F., Foppen, J.W., Gerhards, M.F., Gerven, P., Gooszen, J.A.H., Govaert, J.A., Grevenstein, W.M.U. van, Haen, R., Harlaar, J.J., Harst, E., Havenga, K., Heemskerk, J., Heeren, J.F., Heijnen, B., Heres, P., Hoff, C., Hogendoorn, W., Hoogland, P., Huijbers, A., Janssen, P., Jongen, A.C., Jonker, F.H., Karthaus, E.G., Keijzer, A., Ketel, J.M.A., Klaase, J., Wit, F., Kloppenberg, H., Kool, M.E., Kortekaas, R., Kruyt, P.M., Kuiper, J.T., Lamme, B., Lange, J.F., Lettinga, T., Lips, D.J., Logeman, F., Holzik, M.F.L., Madsen, E., Mamound, A., Marres, C.C., Masselink, I., Meerdink, M., Menon, A.G., Mieog, J.S., Mierlo, D., Musters, G.D., Nieuwenhuijzen, G.A.P., Neijenhuis, P.A., Nonner, J., Oostdijk, M., Paul, P.M.P., Peeters, K.C.M.J., Pereboom, I.T.A., Polat, F., Poortman, P., Raber, M., Reiber, B.M.M., Renger, R.J., Rossem, C.C. van, Rutten, H.J., Rutten, A., Schaapman, R., Scheer, M., Schoonderwoerd, L., Schouten, N., Schreuder, A.M., Schreurs, W.H., Simkens, G.A., Slooter, G.D., Sluijmer, H.C.E., Smakman, N., Smeenk, R., Snijders, H.S., Sonneveld, D.J.A., Spaansen, B., Bilgen, E.J.S., Steller, E., Steup, W.H., Steur, C., Stortelder, E., Straatman, J., Swank, H.A., Sietses, C., Berge, H.A. ten, Hoeve, H.G. ten, Riele, W.W. ter, Thorensen, I.M., Tip-Pluijm, B., Toorenvliet, B.R., Tseng, L., Tuynman, J.B., Bastelaar, J. van, Beek, S.C. van, Ven, A.W.H. van de, Weijer, M.A.J. van de, Berg, C. van den, Bosch, I. van den, Bilt, J.D.W. van der, Hagen, S.J. van der, Hul, R. van der, Schelling, G. van der, Spek, A. van der, Wielen, N. van der, Duyn, E. van, Eekelen, C. van, Essen, J.A. van, Gangelt, K. van, Geloven, A.A.W. van, Kessel, C. van, Loon, Y.T. van, Rijswijk, A. van, Rooijen, S.J. van, Sprundel, T. van, Steensel, L. van, Tets, W.F. van, Veltkamp, S., Verhaak, T., Verheijen, P.M., Versluis-Ossenwaarde, L., Vijfhuize, S., Vles, W.J., Voeten, S.C., Vogelaar, F.J., Vrijland, W.W., Westerduin, E., Westerterp, M.E., Wetzel, M., Wevers, K.P., Wiering, B., Witjes, C.D.M., Wouters, M.W., Yauw, S.T.K., Zaag, E.S. van der, Zeestraten, E.C., Zimmerman, D.D., Zwieten, T., Dutch Snapshot Res Grp, Groningen Institute for Organ Transplantation (GIOT), Value, Affordability and Sustainability (VALUE), ​Robotics and image-guided minimally-invasive surgery (ROBOTICS), CCA - Cancer Treatment and quality of life, Surgery, Amsterdam Reproduction & Development (AR&D), and Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Male, IMPACT, medicine.medical_treatment, THERAPY, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], CHEMORADIATION, 0302 clinical medicine, ADJUVANT CHEMOTHERAPY, Interquartile range, Medicine, PATHOLOGICAL COMPLETE RESPONSE, Stage (cooking), Neoadjuvant therapy, Netherlands, Aged, 80 and over, medicine.diagnostic_test, Incidence, ASO Author Reflections, Chemoradiotherapy, Middle Aged, Magnetic Resonance Imaging, Neoadjuvant Therapy, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Surgical Procedures, Operative, SURVIVAL, 030211 gastroenterology & hepatology, Female, TIME-INTERVAL, RADIOTHERAPY, medicine.medical_specialty, RESECTION, Preoperative care, Time-to-Treatment, 03 medical and health sciences, Preoperative Care, Humans, Survival rate, Aged, Neoplasm Staging, Retrospective Studies, business.industry, Rectal Neoplasms, Magnetic resonance imaging, Retrospective cohort study, NEOADJUVANT CHEMORADIOTHERAPY, Surgery, Cross-Sectional Studies, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

Contains fulltext : 215772.pdf (Publisher’s version ) (Open Access) BACKGROUND: The time interval between CRT and surgery in rectal cancer patients is still the subject of debate. The aim of this study was to first evaluate the nationwide use of restaging magnetic resonance imaging (MRI) and its impact on timing of surgery, and, second, to evaluate the impact of timing of surgery after chemoradiotherapy (CRT) on short- and long-term outcomes. METHODS: Patients were selected from a collaborative rectal cancer research project including 71 Dutch centres, and were subdivided into two groups according to time interval from the start of preoperative CRT to surgery (< 14 and >/= 14 weeks). RESULTS: From 2095 registered patients, 475 patients received preoperative CRT. MRI restaging was performed in 79.4% of patients, with a median CRT-MRI interval of 10 weeks (interquartile range [IQR] 8-11) and a median MRI-surgery interval of 4 weeks (IQR 2-5). The CRT-surgery interval groups consisted of 224 (< 14 weeks) and 251 patients (>/= 14 weeks), and the long-interval group included a higher proportion of cT4 stage and multivisceral resection patients. Pathological complete response rate (n = 34 [15.2%] vs. n = 47 [18.7%], p = 0.305) and CRM involvement (9.7% vs. 15.9%, p = 0.145) did not significantly differ. Thirty-day surgical complications were similar (20.1% vs. 23.1%, p = 0.943), however no significant differences were found for local and distant recurrence rates, disease-free survival, and overall survival. CONCLUSIONS: These real-life data, reflecting routine daily practice in The Netherlands, showed substantial variability in the use and timing of restaging MRI after preoperative CRT for rectal cancer, as well as time interval to surgery. Surgery before or after 14 weeks from the start of CRT resulted in similar short- and long-term outcomes.

Published
2019

7. Propensity score-matched analysis of oncological outcome between stent as bridge to surgery and emergency resection in patients with malignant left-sided colonic obstruction

Author

Amelung, F J, primary, Borstlap, W A A, additional, Consten, E C J, additional, Veld, J V, additional, van Halsema, E E, additional, Bemelman, W A, additional, Siersema, P D, additional, ter Borg, F, additional, van Hooft, J E, additional, Tanis, P J, additional, Algera, H, additional, Algie, G D, additional, Andeweg, C S, additional, Argillander, T, additional, Arron, M N N J, additional, Arts, K, additional, Aufenacker, T H J, additional, Bakker, I S, additional, Basten Batenburg, M, additional, Bastiaansen, A J N M, additional, Beets, G L, additional, Berg, A, additional, Beukel, B, additional, Blom, R L G M, additional, Blomberg, B, additional, Boerma, E G, additional, Boer, F C, additional, Bouvy, N D, additional, Bouwman, J E, additional, Boye, N D A, additional, Brandt, A R M, additional, Brandsma, H T, additional, Breijer, A, additional, Broek, W, additional, Bröker, M E E, additional, Burbach, J P M, additional, Bruns, E R J, additional, Burghgraef, T A, additional, Crolla, R M P H, additional, Dam, M, additional, Daniels, L, additional, Dekker, J W T, additional, Demirkiran, A, additional, Dongen, K, additional, Durmaz, S F, additional, Esch, A, additional, Essen, J A, additional, Foppen, J W, additional, Furnee, E J B, additional, Geloven, A A W, additional, Gerhards, M F, additional, Gorter, E A, additional, Grevenstein, W M U, additional, Groningen, J, additional, Groot, I, additional, Haak, H, additional, Haas, J W A, additional, Hagen, P, additional, Hamminga, J T H, additional, Havenga, K, additional, Hengel, B, additional, Harst, E, additional, Heemskerk, J, additional, Heeren, J, additional, Heijnen, B H M, additional, Heijnen, L, additional, Heikens, J T, additional, Heinsbergen, M, additional, Hess, D A, additional, Heuchemer, N, additional, Hoff, C, additional, Hogendoorn, W, additional, Houdijk, A P J, additional, Hugen, N, additional, Inberg, B, additional, Janssen, T, additional, Pierre, D Jean, additional, Jong, W J, additional, Jongen, A C H M, additional, Kamman, A V, additional, Klaase, J M, additional, Kelder, W, additional, Kelling, E F, additional, Klicks, R, additional, De Klein, G W, additional, Kloppenberg, F W H, additional, Konsten, J L M, additional, Koolen, L J E R, additional, Kornmann, V, additional, Kortekaas, R T J, additional, Kreiter, A, additional, Lamme, B, additional, Lange, J F, additional, Lettinga, T, additional, Lips, D, additional, Lo, G, additional, Logeman, F, additional, Loon, Y T, additional, Holzik, M F Lutke, additional, Marres, C C M, additional, Masselink, I, additional, Mearadji, A, additional, Meisen, G, additional, Menon, A G, additional, Merkus, J, additional, Mey, D, additional, Mijle, H C J, additional, Moes, D E, additional, Molenaar, C, additional, Nieboer, M J, additional, Nielsen, K, additional, Nieuwenhuijzen, G A P, additional, Neijenhuis, P A, additional, Oomen, P, additional, Oorschot, N, additional, Parry, K, additional, Peeters, K C M J, additional, Paulides, T, additional, Paulusma, I, additional, Poelmann, F B, additional, Polle, S W, additional, Poortman, P, additional, Raber, M, additional, Renger, R J, additional, Reiber, B M M, additional, Roukema, R, additional, Ruijter, W M J, additional, Russchen, M J A M, additional, Rutten, H J T, additional, Scheerhoorn, J, additional, Scheurs, S, additional, Schippers, H, additional, Schuermans, V N E, additional, Schuijt, H J, additional, Sierink, J C, additional, Sietses, C, additional, Silvis, R, additional, Slegt, J, additional, Slooter, G, additional, Sluis, M, additional, Sluis, P, additional, Smakman, N, additional, Smit, D, additional, Sprundel, T C, additional, Sonneveld, D J A, additional, Steur, C, additional, Straatman, J, additional, Struijs, M C, additional, Swank, H A, additional, Talsma, A K, additional, Tenhagen, M, additional, Tol, J A M G, additional, Tolenaar, J L, additional, Tseng, L, additional, Tuynman, J B, additional, Veen, M J F, additional, Veltkamp, S, additional, Ven, A W H, additional, Verkoele, L, additional, Vermaas, M, additional, Versteegh, H P, additional, Versluijs, L, additional, Visser, T, additional, Uden, D, additional, Vles, W J, additional, Vos tot Nederveen Cappel, R, additional, Vries, H S, additional, Vugt, S T, additional, Vugts, G, additional, Wegdam, J A, additional, Weijs, T, additional, Wely, B J, additional, Werker, C, additional, Westerterp, M, additional, Westreenen, H L, additional, Wiering, B, additional, Wijffels, N A T, additional, Wijkman, A A, additional, Wijngaarden, L H, additional, Wilt, J H W, additional, Wilt, M, additional, Wisselink, D D, additional, Wit, F, additional, Zaag, E S, additional, Zimmerman, D, additional, and Zwols, T, additional

Published
2019
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8. Benchmarking recent national practice in rectal cancer treatment with landmark randomized controlled trials

Author

Borstlap, W.A., Deijen, C.L., Dulk, M. den, Bonjer, H.J., Velde, C.J. van de, Bemelman, W.A., Tanis, P.J., Aalbers, A., Acherman, Y., Algie, G.D., Geu-sau, B. von, Amelung, F., Aukema, T.S., Bakker, I.S., Bartels, S.A., Basha, S., Bastiaansen, A.J., Belgers, E.H.J., Bleeker, W., Blok, J., Bosker, R.J.I., Bosmans, J.W., Boute, M.C., Bouvy, N.D., Bouwman, H., Brandt-Kerkhof, A., Brinkman, D.J., Bruin, S., Bruns, E.R.J., Burbach, J.P.M., Burger, J.W., Buskens, C.J., Clermonts, S., Coene, P.P.L.O., Compaan, C., Consten, E.C., Darbyshire, T., Mik, S.M.L. de, Graaf, E.J. de, Groot, I de, Cappel de Vos Tot Nederveen, R.J.L., Wilt, J.H.W. de, Wolde, J. van der, Boer, F.C. den, Dekker, J.W.T., Demirkiran, A., Derkx-Hendriksen, M., Dijkstra, F.R., Duijvendijk, P. van, Dunker, M.S., Eijsbouts, Q.E., Fabry, H., Ferenschild, F.T.J., Foppen, J.W., Furnee, E.J.B., Gerhards, M.F., Gerven, P, Gooszen, J.A.H., Govaert, J.A., Grevenstein, W.M. van, Haen, R., Harlaar, J.J., Harst, E, Havenga, K., Heemskerk, J., Heeren, J.F., Heijnen, B., Heres, P., Hoff, C., Hogendoorn, W., Hoogland, P., Huijbers, A, Janssen, P., Jongen, A.C., Jonker, F.H., Karthaus, E.G., Keijzer, A, Ketel, J.M.A., Klaase, J., Kloppenberg, F.W.H., Kool, M.E., Kortekaas, R., Kruyt, P.M., Kuiper, J.T., Lamme, B., Lange, J.F., Lettinga, T., Lips, D.J., Logeman, F., Holzik, M.F., Madsen, E., Mamound, A., Marres, C.C., Masselink, I., Meerdink, M., Menon, A.G., Mieog, J.S., Mierlo, D. van, Musters, G.D., Neijenhuis, P.A., Nonner, J., Oostdijk, M, Oosterling, S.J., Paul, P.M.P., Peeters, K.C., Pereboom, I.T.A., Polat, F., Poortman, P., Raber, M., Reiber, B.M.M., Renger, R.J., Rossem, C.C. van, Rutten, H.J., Rutten, A., Schaapman, R., Scheer, M.G.W., Schoonderwoerd, L., Schouten, N., Schreuder, A.M., Schreurs, W.H., Simkens, G.A., Slooter, G.D., Sluijmer, H.C.E., Smakman, N., Smeenk, R., Snijders, H.S., Sonneveld, D.J.A., Spaansen, B., Spillenaar Bilgen, E.J., Steller, E., Steup, W.H., Steur, C., Stortelder, E., Straatman, J., Swank, H.A., Sietses, C., Berge, H.A. ten, Hoeve, H.G. ten, Riele, W.W. ter, Thorensen, I.M., Tip-Pluijm, B., Toorenvliet, B.R., Tseng, L., Tuynman, J.B., Bastelaar, J. van, Beek, S.V. van, Ven, A.W.H. van de, Weijer, M.A.J. van de, Berg, C. van den, Bosch, I. van den, Bilt, J.D.W. van der, Hagen, S.J. van der, Hul, R. van der, Schelling, G.P. van der, Spek, A van der, Wielen, N. van der, Duyn, E. van, Eekelen, C. van, Essen, J.A. van, Gangelt, K. van, Geloven, A.A. van, Kessel, C. Van, Loon, Y.T. van, Rijswijk, A. van, Rooijen, S.J. van, Sprundel, T. van, Steensel, L. van, Tets, W.F van, Westreenen, H.L. van, Veltkamp, S., Verhaak, T., Verheijen, P.M., Versluis-Ossenwaarde, L., Vijfhuize, S., Vles, W.J., Voeten, S., Vogelaar, F.J., Vrijland, W.W., Westerduin, E., Westerterp, M., Wetzel, M., Wevers, K., Wiering, B., Witjes, A.C., Wouters, M.W., Yauw, S.T.K., Zeestraten, E.C., Zimmerman, D., Zwieten, T., Groningen Institute for Organ Transplantation (GIOT), Value, Affordability and Sustainability (VALUE), ​Robotics and image-guided minimally-invasive surgery (ROBOTICS), Surgery, CCA - Cancer Treatment and quality of life, APH - Quality of Care, APH - Global Health, Anatomy and neurosciences, VU University medical center, AGEM - Re-generation and cancer of the digestive system, AGEM - Digestive immunity, Neurology, Internal medicine, ACS - Microcirculation, MUMC+: MA Heelkunde (9), RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Promovendi MHN, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: NUTRIM - R1 - Metabolic Syndrome, RS: NUTRIM - R2 - Liver and digestive health, Revalidatie, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Promovendi CD, Ondersteunend personeel NTM, Promovendi NTM, Promovendi PHPC, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: MA AIOS Heelkunde (9), Promovendi ODB, MUMC+: MA AIOS Anesthesiologie (9), Pathologie, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA - Cancer Treatment and Quality of Life, Graduate School, and Other departments

Subjects
Male, Transanal Endoscopic Microsurgery, Colorectal cancer, medicine.medical_treatment, NETHERLANDS, law.invention, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 0302 clinical medicine, ADJUVANT CHEMOTHERAPY, Randomized controlled trial, law, Interquartile range, Prospective Studies, Registries, Rectal cancer, Intersectoral Collaboration, Randomized Controlled Trials as Topic, Aged, 80 and over, Medical Audit, Gastroenterology, Margins of Excision, Chemoradiotherapy, Benchmarking, Middle Aged, Total mesorectal excision, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Treatment Outcome, snapshot study, 030220 oncology & carcinogenesis, OPEN SURGERY, Cohort, Female, 030211 gastroenterology & hepatology, RADIOTHERAPY, medicine.medical_specialty, Disease-Free Survival, 03 medical and health sciences, ANTERIOR RESECTION, medicine, Humans, Aged, Retrospective Studies, oncologic outcomes, Rectal Neoplasms, business.industry, General surgery, TOTAL MESORECTAL EXCISION, medicine.disease, Surgery, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Radiation therapy, Cross-Sectional Studies, Circumferential resection margin, Neoplasm Recurrence, Local, business
Abstract

Aim A Snapshot study design eliminates changes in treatment and outcome over time. This population based Snapshot study aimed to determine current practice and outcome of rectal cancer treatment with published landmark randomized controlled trials as a benchmark.Method In this collaborative research project, the dataset of the Dutch Surgical Colorectal Audit was extended with additional treatment and long-term outcome data. All registered patients who underwent resection for rectal cancer in 2011 were eligible. Baseline characteristics and outcome were evaluated against the results of the Dutch TME trial and the COLOR II trial from which the original datasets were obtained.Results A total of 71 hospitals participated, and data were completed for 2102 out of the potential 2633 patients (79.8%). Median follow-up was 41 (interquartile range 25-47) months. Overall circumferential resection margin (CRM) involvement was 9.3% in the Snapshot cohort and 18.5% in the Dutch TME trial. CRM positivity after laparoscopic resection was 7.8% in the Snapshot and 9.5% in the COLOR II trial. Three-year overall local recurrence rate in the Snapshot was 5.9%, with a disease-free survival of 67.1% and overall survival of 79.5%. Benchmarking with the randomized controlled trials revealed an overall favourable long-term outcome of the Snapshot cohort.Conclusion This study showed that current rectal cancer care in a large unselected Dutch population is of high quality, with less positive CRM since the TME trial and oncologically safe implementation of minimally invasive surgery after the COLOR II trial.

Published
2017

9. Benchmarking recent national practice in rectal cancer treatment with landmark randomized controlled trials

Author

Borstlap, W.A.A., Deijen, C.L., Dulk, M. den, Bonjer, H.J., Velde, C.J. van de, Bemelman, W.A., Tanis, P.J., Aalbers, A., Acherman, Y., Algie, G.D., Geu-sau, B.A. von, Amelung, F., Aukema, T.S., Bakker, I.S., Bartels, S.A., Basha, S., Bastiaansen, A.J.N.M., Belgers, E., Bleeker, W., Blok, J., Bosker, R.J.I., Bosmans, J.W., Boute, M.C., Bouvy, N.D., Bouwman, H., Brandt-Kerkhof, A., Brinkman, D.J., Bruin, S., Bruns, E.R.J., Burbach, J.P.M., Burger, J.W.A., Buskens, C.J., Clermonts, S., Coene, P.P.L.O., Compaan, C., Consten, E.C.J., Darbyshire, T., Mik, S.M.L. de, Graaf, E.J.R. de, Groot, I. de, Cappel, R.J.L.D.T.N., Wilt, J.H.W. de, Wolde, J. van der, Boer, F.C. den, Dekker, J.W.T., Demirkiran, A., Derkx-Hendriksen, M., Dijkstra, F.R., Duijvendijk, P. van, Dunker, M.S., Eijsbouts, Q.E., Fabry, H., Ferenschild, F., Foppen, J.W., Furnee, E.J.B., Gerhards, M.F., Gerven, P., Gooszen, J.A.H., Govaert, J.A., Grevenstein, W.M.U. van, Haen, R., Harlaar, J.J., Harst, E., Havenga, K., Heemskerk, J., Heeren, J.F., Heijnen, B., Heres, P., Hoff, C., Hogendoorn, W., Hoogland, P., Huijbers, A., Janssen, P., Jongen, A.C., Jonker, F.H., Karthaus, E.G., Keijzer, A., Ketel, J.M.A., Klaase, J., Kloppenberg, F.W.H., Kool, M.E., Kortekaas, R., Kruyt, P.M., Kuiper, J.T., Lamme, B., Lange, J.F., Lettinga, T., Lips, D.J., Logeman, F., Holzik, M.F.L., Madsen, E., Mamound, A., Marres, C.C., Masselink, I., Meerdink, M., Menon, A.G., Mieog, J.S., Mierlo, D., Musters, G.D., Neijenhuis, P.A., Nonner, J., Oostdijk, M., Oosterling, S.J., Paul, P.M.P., Peeters, K.C.M.J.C., Pereboom, I.T.A., Polat, F., Poortman, P., Raber, M., Reiber, B.M.M., Renger, R.J., Rossem, C.C. van, Rutten, H.J., Rutten, A., Schaapman, R., Scheer, M., Schoonderwoerd, L., Schouten, N., Schreuder, A.M., Schreurs, W.H., Simkens, G.A., Slooter, G.D., Sluijmer, H.C.E., Smakman, N., Smeenk, R., Snijders, H.S., Sonneveld, D.J.A., Spaansen, B., Bilgen, E.J.S., Steller, E., Steup, W.H., Steur, C., Stortelder, E., Straatman, J., Swank, H.A., Sietses, C., Berge, H.A. ten, Hoeve, H.G. ten, Riele, W.W. ter, Thorensen, I.M., Tip-Pluijm, B., Toorenvliet, B.R., Tseng, L., Tuynman, J.B., Bastelaar, J. van, Beek, S.V. van, Ven, A.W.H. van de, Weijer, M.A.J. van de, Berg, C. van den, Bosch, I. van den, Bilt, J.D.W. van der, Hagen, S.J. van der, Hul, R. van der, Schelling, G. van der, Spek, A. van der, Wielen, N. van der, Duyn, E. van, Eekelen, C. van, Essen, J.A. van, Gangelt, K. van, Geloven, A.A.W. van, Kessel, C. van, Loon, Y.T. van, Rijswijk, A. van, Rooijen, S.J. van, Sprundel, T. van, Steensel, L. van, Tets, W.F. van, Westreenen, H.L. van, Veltkamp, S., Verhaak, T., Verheijen, P.M., Versluis-Ossenwaarde, L., Vijfhuize, S., Vles, W.J., Voeten, S., Vogelaar, F.J., Vrijland, W.W., Westerduin, E., Westerterp, M.E., Wetzel, M., Wevers, K., Wiering, B., Witjes, A.C., Wouters, M.W., Yauw, S.T.K., Zeestraten, E.C., Zimmerman, D.D., Zwieten, T., and Dutch Snapshot Res Grp

Subjects
oncologic outcomes, snapshot study, Rectal cancer
Abstract

Aim A Snapshot study design eliminates changes in treatment and outcome over time. This population based Snapshot study aimed to determine current practice and outcome of rectal cancer treatment with published landmark randomized controlled trials as a benchmark.Method In this collaborative research project, the dataset of the Dutch Surgical Colorectal Audit was extended with additional treatment and long-term outcome data. All registered patients who underwent resection for rectal cancer in 2011 were eligible. Baseline characteristics and outcome were evaluated against the results of the Dutch TME trial and the COLOR II trial from which the original datasets were obtained.Results A total of 71 hospitals participated, and data were completed for 2102 out of the potential 2633 patients (79.8%). Median follow-up was 41 (interquartile range 25-47) months. Overall circumferential resection margin (CRM) involvement was 9.3% in the Snapshot cohort and 18.5% in the Dutch TME trial. CRM positivity after laparoscopic resection was 7.8% in the Snapshot and 9.5% in the COLOR II trial. Three-year overall local recurrence rate in the Snapshot was 5.9%, with a disease-free survival of 67.1% and overall survival of 79.5%. Benchmarking with the randomized controlled trials revealed an overall favourable long-term outcome of the Snapshot cohort.Conclusion This study showed that current rectal cancer care in a large unselected Dutch population is of high quality, with less positive CRM since the TME trial and oncologically safe implementation of minimally invasive surgery after the COLOR II trial.

Published
2017

14. Ecologisch profiel van het Nonnetje (Macoma balthica)

Author

Steur, C. (author), Seys, J. (author), Eppinga, J. (author), Steur, C. (author), Seys, J. (author), and Eppinga, J. (author)

Abstract

(See below for English summary) Het Nonnetje (Macoma balthica) is een voor de ondiepe kustwateren van Nederland karakteristiel tweekleppig schelpdier dat ondiep ingegraven in de bodem leeft. Vooral op de bij laag water droog vallende platen in het Waddenzeegebied en in Ooster- en Westerschelde is het een belangrijke soort. Het Nonnetje is in het project Watersysteemverkenningen (WSV) gekozen als doelvariabele om de milieukwaliteit van de Nederlandse zoute wateren te toetsen. In het Ecoprofiel komt naar voren dat dichtheid en biomassa van het Nonnetje beïnvloedbaar zijn door de mate van eutrofiëring van onze kustwateren. Zo wordt de in de laatste decennia toegenomen dichtheid en biomassa in de westelijke Waddenzee in verband gebracht met eutrofiëring door afvoer van voedingsstoffen (o.a. vanuit het IJsselmeer). In het oostelijk deel van de Westerschelde heeft verontreiniging een nadelige invloed gehad op de ontwikkeling van populaties van het Nonnetje. Oudere dieren ontbreken hier nagenoeg. Storten van baggerspecie heeft pas dan negatief effect op lokaal aanwezige Nonnetjes als meer dan 10 cm slib wordt afgezet. Ze raken dan definitief begraven en overleven niet. -English- The Baltic Tellin (Macoma balthica) is a characteristic and common bivalve mollusc in Dutch coastal waters. It lives shallowly buried in the sediment, and is especially abundant at intertidal flats in Wadden Sea, Oosterschelde and Westerschelde. In the 'Aquatic Outlook' project the species was chosen as a sentinel organism for measuring environmental quality of coastal waters. The data compiled in this document suggest that abundance and biomass of Macoma balthica may be dependent of the degree of eutrophication of our coastal waters. In fact, the increase in abundance and biomass during the last t w o decades observed in the western Dutch Wadden Sea has been related to the discharge of nutrients f r om lake IJsselmeer. In the eastern part of the Westerschelde pollution had a negative effect on the, Watersysteemverkenningen (WSV) 1996

Published
1996

15. Ecologisch profiel van de Strandgaper (Mya arenaria)

Author

Steur, C. (author), Seys, J. (author), Eppinga, J. (author), Steur, C. (author), Seys, J. (author), and Eppinga, J. (author)

Abstract

(See below for English summary. Content of rapport is in Dutch) De Strandgaper (Mya arenaria) is een in de ondiepe kustwateren van Nederland algemeen tweekleppig schelpdier dat tot 40 cm diep ingegraven in de bodem leeft. Vooral op de bij laag water droog vallende platen in het Waddenzeegebied en in Ooster- en Westerschelde is het een belangrijke soort. In de ondiepe kustzone is de soort aanzienlijk minder talrijk. De soort voedt zich met partikeltjes van uiteenlopende aard (vooral flagellaten en detritus) die uit het water worden gefiltreerd. De Strandgaper is in het project Watersysteemverkenningen (WSV) gekozen als doelvariabele om de milieukwaliteit van de Nederlandse zoute wateren te toetsen. In het Ecoprofiel komt naar voren dat het voorkomen van de Strandgaper negatief beïnvloed wordt door diverse verontreinigingen en het storten van baggerspecie. Organische microverontreinigingen kunnen het ontstaan van tumorcellen induceren. Het geringe voorkomen van de Strandgaper in het oostelijk deel van de Westerschelde moet in verband worden gebracht met daar voorkomende concentraties microverontreinigingen. Storten van baggerspecie heeft pas dan negatief effect op lokaal aanwezige Strandgapers als meer dan 8 cm slib wordt afgezet. -English- The soft shell clam (Mya arenaria) is a common bivalve mollusc in shallow Dutch coastal waters. It lives in the sediment at depths down to 40 cm. It is especially abundant at intertidal flats in the Wadden Sea, Ems estuary, Westerschelde and Oosterschelde. In coastal waters the species is far less abundant. The species is a suspension feeder utilising various particles, such as phytoplankton and detritus, from the water column. In the 'Aquatic Outlook' project Mya arenaria has been chosen as a sentinel organism for measuring environmental quality of coastal waters. The occurrence of Mya arenaria can be negatively influenced by various pollutants as well as by dumping of dredged material. Organic micropollutants are considered as a, Watersysteemverkenningen (WSV) 1996

Published
1996

16. Ecologische profielen: bodemdieren, nonnetje Macoma balthica, kokkel Cerastoderme edule, strandgaper Mya arenaria, mossel Mytilus edulis, Zeeuwse oester Ostrea edulis, zeeklit Echinocardium cordatum, zeeanjelier Metridium senile, in Nederlandse zoute wateren

Author

Steur, C. and Seys, J.

Subjects
Echinocardium cordatum (Pennant, 1777), ANE, Netherlands, Ecology, Cerastoderma edule (Linnaeus, 1758) [Common cockle], Mya arenaria Linnaeus, 1758, Metridium senile (Linnaeus, 1761), Ostrea edulis Linnaeus, 1758, Mytilus edulis Linnaeus, 1758, Macoma balthica (Linnaeus, 1758)
Published
1988

17. Antibody Response to COVID-19 mRNA Vaccine in Patients With Lung Cancer After Primary Immunization and Booster: Reactivity to the SARS-CoV-2 WT Virus and Omicron Variant.

Author

Valanparambil RM, Carlisle J, Linderman SL, Akthar A, Millett RL, Lai L, Chang A, McCook-Veal AA, Switchenko J, Nasti TH, Saini M, Wieland A, Manning KE, Ellis M, Moore KM, Foster SL, Floyd K, Davis-Gardner ME, Edara VV, Patel M, Steur C, Nooka AK, Green F, Johns MA, O'Brein F, Shanmugasundaram U, Zarnitsyna VI, Ahmed H, Nyhoff LE, Mantus G, Garett M, Edupuganti S, Behra M, Antia R, Wrammert J, Suthar MS, Dhodapkar MV, Ramalingam S, and Ahmed R

Subjects
Humans, Aged, COVID-19 Vaccines, Antibody Formation, SARS-CoV-2, Antibodies, Viral, Immunization, Vaccination, Antibodies, Neutralizing, RNA, Messenger, mRNA Vaccines, Carcinoma, Non-Small-Cell Lung therapy, Lung Neoplasms therapy, COVID-19 prevention & control
Abstract

Purpose: To examine COVID-19 mRNA vaccine-induced binding and neutralizing antibody responses in patients with non-small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the primary 2-dose and booster vaccination., Methods: Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively., Results: A majority of patients with NSCLC generated binding and neutralizing antibody titers comparable with the healthy vaccinees after mRNA vaccination, but a subset of patients with NSCLC (25%) made poor responses, resulting in overall lower (six- to seven-fold) titers compared with the healthy cohort ( P = < .0001). Although patients age > 70 years had lower immunoglobulin G titers ( P = < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a combination of both did not have a significant impact on the antibody response. Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in particular, B.1.1.529 (Omicron) variants were significantly lower ( P = < .0001) compared with the 614D (WT) strain. Booster vaccination led to a significant increase ( P = .0001) in the binding and neutralizing antibody titers to the WT and Omicron variant. However, 2-4 months after the booster, we observed a five- to seven-fold decrease in neutralizing titers to WT and Omicron viruses., Conclusion: A subset of patients with NSCLC responded poorly to the SARS-CoV-2 mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron variant. Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant.

Published
2022
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18. Antibody response to SARS-CoV-2 mRNA vaccine in lung cancer patients: Reactivity to vaccine antigen and variants of concern.

Author

Valanparambil R, Carlisle J, Linderman S, Akthar A, Millett RL, Lai L, Chang A, McCook A, Switchenko J, Nasti T, Saini M, Andreas Wieland AW, Manning K, Ellis M, Moore K, Foster S, Floyd K, Davis-Gardner M, Viswanadh Edara V, Patel M, Steur C, Nooka A, Green F, Johns M, O Brein F, Shanmugasundaram U, Zarnitsyna V, Ahmed H, Nyhoff L, Mantus G, Garett M, Edupuganti S, Behra M, Antia R, Wrammert J, Suthar M, Dhodapkar M, Ramalingam S, and Ahmed R

Abstract

Purpose: We investigated SARS-CoV-2 mRNA vaccine-induced binding and live-virus neutralizing antibody response in NSCLC patients to the SARS-CoV-2 wild type strain and the emerging Delta and Omicron variants., Methods: 82 NSCLC patients and 53 healthy adult volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and live-virus neutralization response to 614D (WT), B.1.617.2 (Delta), B.1.351 (Beta) and B.1.1.529 (Omicron) variants were evaluated by Meso Scale Discovery (MSD) assay and Focus Reduction Neutralization Assay (FRNT) respectively. We determined the longevity and persistence of vaccine-induced antibody response in NSCLC patients. The effect of vaccine-type, age, gender, race and cancer therapy on the antibody response was evaluated., Results: Binding antibody titer to the mRNA vaccines were lower in the NSCLC patients compared to the healthy volunteers (P=<0.0001). More importantly, NSCLC patients had reduced live-virus neutralizing activity compared to the healthy vaccinees (P=<0.0001). Spike and RBD-specific binding IgG titers peaked after a week following the second vaccine dose and declined after six months (P=<0.001). While patients >70 years had lower IgG titers (P=<0.01), patients receiving either PD-1 monotherapy, chemotherapy or a combination of both did not have a significant impact on the antibody response. Binding antibody titers to the Delta and Beta variants were lower compared to the WT strain (P=<0.0001). Importantly, we observed significantly lower FRNT50 titers to Delta (6-fold), and Omicron (79-fold) variants (P=<0.0001) in NSCLC patients., Conclusions: Binding and live-virus neutralizing antibody titers to SARS-CoV-2 mRNA vaccines in NSCLC patients were lower than the healthy vaccinees, with significantly lower live-virus neutralization of B.1.617.2 (Delta), and more importantly, the B.1.1.529 (Omicron) variant compared to the wild-type strain. These data highlight the concern for cancer patients given the rapid spread of SARS-CoV-2 Omicron variant.

Published
2022
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19. Hemolysis is associated with low reticulocyte production index and predicts blood transfusion in severe malarial anemia.

Author

Fendel R, Brandts C, Rudat A, Kreidenweiss A, Steur C, Appelmann I, Ruehe B, Schröder P, Berdel WE, Kremsner PG, and Mordmüller B

Subjects
Anemia therapy, Biomarkers, Case-Control Studies, Child, Erythrocyte Aging, Humans, Malaria blood, Malaria therapy, Plasmodium falciparum, Severity of Illness Index, Anemia etiology, Blood Transfusion, Hemolysis, Malaria pathology, Reticulocytes cytology
Abstract

Background: Falciparum Malaria, an infectious disease caused by the apicomplexan parasite Plasmodium falciparum, is among the leading causes of death and morbidity attributable to infectious diseases worldwide. In Gabon, Central Africa, one out of four inpatients have severe malarial anemia (SMA), a life-threatening complication if left untreated. Emerging drug resistant parasites might aggravate the situation. This case control study investigates biomarkers of enhanced hemolysis in hospitalized children with either SMA or mild malaria (MM)., Methods and Findings: Ninety-one children were included, thereof 39 SMA patients. Strict inclusion criteria were chosen to exclude other causes of anemia. At diagnosis, erythrophagocytosis (a direct marker for extravascular hemolysis, EVH) was enhanced in SMA compared to MM patients (5.0 arbitrary units (AU) (interquartile range (IR): 2.2-9.6) vs. 2.1 AU (IR: 1.3-3.9), p<0.01). Furthermore, indirect markers for EVH, (i.e. serum neopterin levels, spleen size enlargement and monocyte pigment) were significantly increased in SMA patients. Markers for erythrocyte ageing, such as CD35 (complement receptor 1), CD55 (decay acceleration factor) and phosphatidylserine exposure (annexin-V-binding) were investigated by flow cytometry. In SMA patients, levels of CD35 and CD55 on the red blood cell surface were decreased and erythrocyte removal markers were increased when compared to MM or reconvalescent patients. Additionally, intravascular hemolysis (IVH) was quantified using several indirect markers (LDH, alpha-HBDH, haptoglobin and hemopexin), which all showed elevated IVH in SMA. The presence of both IVH and EVH predicted the need for blood transfusion during antimalarial treatment (odds ratio 61.5, 95% confidence interval (CI): 8.9-427). Interestingly, this subpopulation is characterized by a significantly lowered reticulocyte production index (RPI, p<0.05)., Conclusions: Our results show the multifactorial pathophysiology of SMA, whereby EVH and IVH play a particularly important role. We propose a model where removal of infected and non-infected erythrocytes of all ages (including reticulocytes) by EVH and IVH is a main mechanism of SMA. Further studies are underway to investigate the mechanism and extent of reticulocyte removal to identify possible interventions to reduce the risk of SMA development.

Published
2010
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20. New method to quantify erythrophagocytosis by autologous monocytes.

Author

Fendel R, Mordmüller B, Kreidenweiss A, Rudat A, Steur C, Ambrosch C, Kirstein M, Berdel WE, Kremsner PG, and Brandts C

Subjects
Anemia metabolism, Fluoresceins metabolism, Fluorescent Dyes metabolism, Humans, Lipopolysaccharide Receptors immunology, Succinimides metabolism, Erythrocytes metabolism, Flow Cytometry methods, Microscopy, Fluorescence methods, Monocytes metabolism, Phagocytosis
Abstract

Background: Anemia is the net result of decreased red blood cell (RBC) production and increased removal of RBCs. Replication and maturation of erythroid precursors and RBC lysis can be measured by standardized in vitro methods and surrogate markers, respectively. In contrast, erythrophagocytosis by autologous phagocytes is more difficult to quantify., Methods: We developed a method to assess erythrophagocytosis by autologous monocytes from 5 ml of whole blood. RBCs were labeled with carboxyfluorescein-diacetate-succinimidyl ester (CFDA-SE) and subsequently coincubated with autologous CD14(+) monocytes. Phagocytosis was quantified using flow cytometry. After standardization, the assay was validated in patients with severe malarial anemia (SMA), a condition that is associated with increased erythrophagocytosis., Results: After labeling, CFDA-SE was stably incorporated into RBCs and no significant leakage leading to contamination of nonlabeled cells was observed. Monocytes ingested opsonized, labeled RBCs seven times more than nonopsonized controls. Erythrophagocytosis was significantly higher in SMA than in healthy controls., Conclusions: The established assay showed enhanced autoerythrophagocytosis associated with SMA and hence was able to detect clinically relevant erythrophagocytosis. This novel assay is well suited for rapid quantification of in vitro erythrophagocytosis by autologous monocytes., ((c) 2007 International Society for Analytical Cytology.)

Published
2007
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21. RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.

Author

Schwäble J, Choudhary C, Thiede C, Tickenbrock L, Sargin B, Steur C, Rehage M, Rudat A, Brandts C, Berdel WE, Müller-Tidow C, and Serve H

Subjects
Acute Disease, Cell Differentiation, Cell Line, Cell Proliferation, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, HL-60 Cells, Humans, Leukemia, Myeloid etiology, Phosphorylation, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Repressor Proteins, Tandem Repeat Sequences, fms-Like Tyrosine Kinase 3, Cell Transformation, Neoplastic, Leukemia, Myeloid genetics, Mutation, Myeloid Cells pathology, Proto-Oncogene Proteins genetics, RGS Proteins genetics, Receptor Protein-Tyrosine Kinases genetics
Abstract

Activating fetal liver tyrosine kinase 3 (Flt3) mutations represent the most common genetic aberrations in acute myeloid leukemia (AML). Most commonly, they occur as internal tandem duplications in the juxtamembrane domain (Flt3-ITD) that transform myeloid cells in vitro and in vivo and that induce aberrant signaling and biologic functions. We identified RGS2, a regulator of G-protein signaling, as a gene specifically repressed by Flt3-ITD. Here we demonstrate an important role of RGS2 in Flt3-ITD-mediated transformation. RGS2 was repressed after forced expression of activating Flt3 mutations in 2 myeloid cell lines (32Dcl3 and NB4). Furthermore, RGS2 was repressed in Flt3-mutation-positive AML cases in comparison to Flt3-mutation-negative cases, especially in Flt3-ITD-positive cases with a high ITD-to-wild-type (WT) ratio. Coexpression of RGS2 with Flt3-ITD inhibited Flt3-ITD-induced autonomous proliferation and clonal growth of 32D cells. RGS2 also inhibited Flt3-ITD-induced phosphorylation of Akt and glycogen synthase kinase beta (Gsk3-beta) without influencing signal transducer and activator of transcription 5 (STAT5) activation. In addition, RGS2 reinduced the expression of Flt3-ITD-repressed CCAAT/enhancer-binding protein alpha (c/EBPalpha) and antagonized the Flt3-ITD-induced differentiation block in 32D cells. Expression analyses in myeloid cell lines revealed induction of RGS2 during granulocytic but not during monocytic differentiation. Taken together, RGS2 is a novel mediator of myeloid differentiation, and its repression is an important event in Flt3-ITD-induced transformation.

Published
2005
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22. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.

Author

Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, Steffen B, Matsumura I, Kanakura Y, Böhmer FD, Müller-Tidow C, Berdel WE, and Serve H

Subjects
Acute Disease, Animals, CCAAT-Enhancer-Binding Protein-alpha biosynthesis, CCAAT-Enhancer-Binding Protein-alpha genetics, Cell Line metabolism, Cluster Analysis, Computer Systems, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genes, Synthetic, Hematopoietic Stem Cells metabolism, Humans, Interleukin-3 pharmacology, Leukemia, Myeloid pathology, Mice, Myeloid Cells metabolism, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Oligonucleotide Array Sequence Analysis, Protein Isoforms physiology, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins physiology, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators biosynthesis, Trans-Activators genetics, Transfection, fms-Like Tyrosine Kinase 3, Gene Expression Regulation, Leukemia, Myeloid genetics, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins physiology, Receptor Protein-Tyrosine Kinases physiology, Tandem Repeat Sequences, Transcription, Genetic
Abstract

The receptor tyrosine kinase Flt3 is expressed and functionally important in early myeloid progenitor cells and in the majority of acute myeloid leukemia (AML) blasts. Internal tandem duplications (ITDs) in the juxtamembrane domain of the receptor occur in 25% of AML cases. Previously, we have shown that these mutations activate the receptor and induce leukemic transformation. In this study, we performed genome-wide parallel expression analyses of 32Dcl3 cells stably transfected with either wild-type or 3 different ITD isoforms of Flt3. Comparison of microarray expression analyses revealed that 767 of 6586 genes differed in expression between FLT3-WT- and FLT3-ITD-expressing cell lines. The target genes of mutationally activated Flt3 resembled more closely those of the interleukin 3 (IL-3) receptor than those of ligand-activated Flt3. The serine-threonine kinase Pim-2 was up-regulated on the mRNA and the protein level in Flt3-ITD-expressing cells. Further experiments indicated that Pim-2 function was important for clonal growth of 32D cells. Several genes repressed by the mutations were found to be involved in myeloid gene regulation. Pu.1 and C/EBPalpha, both induced by ligand-activation of wild-type Flt3, were suppressed in their expression and function by the Flt3 mutations. In conclusion, internal tandem duplication mutations of Flt3 activate transcriptional programs that partially mimic IL-3 activity. Interestingly, other parts of the transcriptional program involve novel, IL-3-independent pathways that antagonize differentiation-inducing effects of wild-type Flt3. The identification of the transcriptional program induced by ITD mutations should ease the development of specific therapies.

Published
2003
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23. [Mutations of growth factor receptor Flt3 in acute myeloid leukemia: transformation of myeloid cells by Ras-dependent and Ras-independent mechanisms].

Author

Müller-Tidow C, Steur C, Mizuki M, Schwäble J, Brandts C, Berdel WE, and Serve H

Subjects
Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis genetics, Cell Division drug effects, Cell Division genetics, Gene Expression Regulation, Leukemic physiology, Humans, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System genetics, Phosphoinositide-3 Kinase Inhibitors, Prognosis, RNA, Messenger genetics, Signal Transduction genetics, Tumor Cells, Cultured, fms-Like Tyrosine Kinase 3, ras Proteins antagonists & inhibitors, ras Proteins physiology, Cell Transformation, Neoplastic genetics, Leukemia, Myeloid, Acute genetics, Mutation genetics, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, ras Proteins genetics
Abstract

Background and Objective: The tyrosine kinase receptor Flt3 mediates important functions in early hematopoietic progenitors. Recently mutations of a growth factor receptor have been identified in about 30 % of patients with acute myeloid leukemia (AML). These mutations are associated with a poor prognosis. In-vitro and animal data show their involvement in leukemic transformation. Experiments analyzing the effects of these mutations on signal transduction and gene expression patterns of myeloid cells allow for the classification of this receptor as an oncogene. Furthermore, they help to define the receptor and its signaling intermediates as therapeutic targets., Methods: In order to analyze the signaling properties of mutated FLT3 receptors, we isolated the receptor mRNA from two patients with AML. Wild-type and mutant Flt3 isoforms were expressed in 32D cells that were subsequently analyzed for proliferation, survival, activation of signaling intermediates and gene expression levels. Also, the effects of of Ras-, MAP-Kinase and PI3-Kinase inhibition were analyzed., Results: The expression of mutated Flt3 (Flt3-ITD) induced factor-independent proliferation and survival in the myeloid progenitor cell line 32D. Flt3-ITD activated Ras- and PI3-kinase-dependent signaling pathways, as well as STAT5 and STAT3. Activation of STAT proteins was followed by the induction of known STAT target genes like SOCS2, SOCS3 and CIS. Inhibition of Ras-dependent signal transduction by a dominant negative Ras construct inhibited some, but not all biological effects of Flt3-ITD. Similar results were obtained by chemical inhibition of the MAP kinases. In contrast, inhibition of PI3 kinase activity inhibited growth factor-independent growth and apoptosis resistance of 32D cells., Conclusions: Inhibition of Ras-dependent signaling pathways is not sufficient to abrogate the functional consequences of Flt3-mutations in myeloid cells. Therefore, therapeutic intervention by Ras-Inhibitors may not be sufficient to treat Flt3-driven disease.

Published
2002
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24. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.

Author

Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Müller C, Grüning W, Kratz-Albers K, Serve S, Steur C, Büchner T, Kienast J, Kanakura Y, Berdel WE, and Serve H

Subjects
Acute Disease, Animals, Apoptosis drug effects, Apoptosis radiation effects, Cell Division drug effects, Clone Cells cytology, DNA Replication drug effects, DNA-Binding Proteins metabolism, DNA-Binding Proteins physiology, Female, Humans, Leukemia, Myeloid genetics, Mice, Mice, Inbred C3H, Mitogen-Activated Protein Kinase Kinases metabolism, Mutation, Myeloid Cells drug effects, Myeloid Cells physiology, Neoplasms, Experimental mortality, Neoplasms, Experimental pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Receptor Protein-Tyrosine Kinases metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Recombinant Fusion Proteins pharmacology, STAT5 Transcription Factor, Signal Transduction drug effects, Tandem Repeat Sequences genetics, Trans-Activators metabolism, Trans-Activators physiology, Transfection, Tumor Cells, Cultured, fms-Like Tyrosine Kinase 3, ras Proteins metabolism, ras Proteins physiology, Cell Transformation, Neoplastic drug effects, Leukemia, Myeloid physiopathology, Milk Proteins, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins pharmacology, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases pharmacology
Abstract

Somatic mutations of the receptor tyrosine kinase Flt3 consisting of internal tandem duplications (ITD) occur in 20% of patients with acute myeloid leukemia. They are associated with a poor prognosis of the disease. In this study, we characterized the oncogenic potential and signaling properties of Flt3 mutations. We constructed chimeric molecules that consisted of the murine Flt3 backbone and a 510-base pair human Flt3 fragment, which contained either 4 different ITD mutants or the wild-type coding sequence. Flt3 isoforms containing ITD mutations (Flt3-ITD) induced factor-independent growth and resistance to radiation-induced apoptosis in 32D cells. Cells containing Flt3-ITD, but not those containing wild-type Flt3 (Flt3-WT), formed colonies in methylcellulose. Injection of 32D/Flt3-ITD induced rapid development of a leukemia-type disease in syngeneic mice. Flt3-ITD mutations exhibited constitutive autophosphorylation of the immature form of the Flt3 receptor. Analysis of the involved signal transduction pathways revealed that Flt3-ITD only slightly activated the MAP kinases Erk1 and 2 and the protein kinase B (Akt) in the absence of ligand and retained ligand-induced activation of these enzymes. However, Flt3-ITD led to strong factor-independent activation of STAT5. The relative importance of the STAT5 and Ras pathways for ITD-induced colony formation was assessed by transfection of dominant negative (dn) forms of these proteins: transfection of dnSTAT5 inhibited colony formation by 50%. Despite its weak constitutive activation by Flt3-ITD, dnRas also strongly inhibited Flt3-ITD-mediated colony formation. Taken together, Flt3-ITD mutations induce factor-independent growth and leukemogenesis of 32D cells that are mediated by the Ras and STAT5 pathways. (Blood. 2000;96:3907-3914)

Published
2000

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