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1. Rapid and automated design of two-component protein nanomaterials using ProteinMPNN

Author

de Haas, Robbert J, Brunette, Natalie, Goodson, Alex, Dauparas, Justas, Yi, Sue Y, Yang, Erin C, Dowling, Quinton, Nguyen, Hannah, Kang, Alex, Bera, Asim K, Sankaran, Banumathi, de Vries, Renko, Baker, David, and King, Neil P

Subjects
Biochemistry and Cell Biology, Biological Sciences, Bioengineering, Biotechnology, Generic health relevance, Models, Molecular, Proteins, Amino Acid Sequence, Nanostructures, Protein Conformation, ProteinMPNN, nanomaterials, protein design
Abstract

The design of protein-protein interfaces using physics-based design methods such as Rosetta requires substantial computational resources and manual refinement by expert structural biologists. Deep learning methods promise to simplify protein-protein interface design and enable its application to a wide variety of problems by researchers from various scientific disciplines. Here, we test the ability of a deep learning method for protein sequence design, ProteinMPNN, to design two-component tetrahedral protein nanomaterials and benchmark its performance against Rosetta. ProteinMPNN had a similar success rate to Rosetta, yielding 13 new experimentally confirmed assemblies, but required orders of magnitude less computation and no manual refinement. The interfaces designed by ProteinMPNN were substantially more polar than those designed by Rosetta, which facilitated in vitro assembly of the designed nanomaterials from independently purified components. Crystal structures of several of the assemblies confirmed the accuracy of the design method at high resolution. Our results showcase the potential of deep learning-based methods to unlock the widespread application of designed protein-protein interfaces and self-assembling protein nanomaterials in biotechnology.

Published
2024

8. Prognostic significance of MRI-detected extramural venous invasion according to grade and response to neo-adjuvant treatment in locally advanced rectal cancer A national cohort study after radiologic training and reassessment

Author

Aalbers, Arend G.J., van Aalten, Susanna M., Amelung, Femke J., Ankersmit, Marjolein, Antonisse, Imogeen E., Ashruf, Jesse F., Aukema, Tjeerd S., Avenarius, Henk, Bahadoer, Renu R., Bakers, Frans C.H., Bakker, Ilsalien S., Bangert, Fleur, Barendse, Renée M., Beekhuis, Heleen M.D., Beets, Geerard L., Bemelman, Willem A., Berbée, Maaike, de Bie, Shira H., Bisschops, Robert H.C., Blok, Robin D., van Bockel, Liselotte W., Boer, Anniek H., den Boer, Frank C., Boerma, Evert-Jan G., Boogerd, Leonora S.F., Borstlap, Jaap, Borstlap, Wernard A.A., Bouwman, Johanna E., Braak, Sicco J., Braat, Manon N.G.J.A., Bradshaw, Jennifer, Brandsma, Amarins T.A., van Breest Smallenburg, Vivian, van den Broek, Wim T., van der Burg, Sjirk W., Burger, Jacobus W.A., Burghgraef, Thijs A., ten Cate, David W.G., Ceha, Heleen M., Cnossen, Jeltsje S., Coebergh van den Braak, Robert R.J., Consten, Esther C.J., Corver, Maaike, Crolla, Rogier M.P.H., Curutchet, Sam, Daniëls-Gooszen, Alette W., Davids, Paul H.P., Dekker, Emmelie N., Dekker, Jan Willem T., Demirkiran, Ahmet, Derksen, Tyche, Diederik, Arjen L., Dinaux, Anne M., Dogan, Kemal, van Dop, Ilse M., Droogh-de Greve, Kitty E., Duijsens, Hanneke M.H., Dunker, Michalda S., Duyck, Johan, van Duyn, Eino B., van Egdom, Laurentine S.E., Eijlers, Bram, El-Massoudi, Youssef, van Elderen, Saskia, Emmen, Anouk M.L.H., Engelbrecht, Marc, van Erp, Anne C., van Essen, Jeroen A., Fabry, Hans F.J., Fassaert, Thomas, Feitsma, Eline A., Feshtali, Shirin S., Frietman, Bas, Furnée, Edgar J.B., van Geel, Anne M., Geijsen, Elisabeth D., van Geloven, Anna A.W., Gerhards, Michael F., Gielkens, Hugo, van Gils, Renza A.H., Goense, Lucas, Govaert, Marc J.P.M., van Grevenstein, Wilhelmina M.U., Joline de Groof, E., de Groot, Irene, de Haas, Robbert J., Hakkenbrak, Nadia A.G., den Hartogh, Mariska D., Heesink, Vera, Heikens, Joost T., Hendriksen, Ellen M., van den Hoek, Sjoerd, van der Hoeven, Erik J.R.J., Hoff, Christiaan, Hogewoning, Anna, Hogewoning, Cornelis R.C., Hoogendoorn, Stefan, van Hoorn, Francois, van der Hul, René L., van Hulst, Rieke, Imani, Farshad, Inberg, Bas, Intven, Martijn P.W., Janssen, Pedro, de Jong, Chris E.J., Jonkers, Jacoline, Jou-Valencia, Daniela, Keizers, Bas, Ketelaers, Stijn H.J., Knöps, Eva, van Koeverden, Sebastiaan, Kok, Sylvia, Kolderman, Stephanie E.M., de Korte, Fleur I., Kortekaas, Robert T.J., Korving, Julie C., Koster, Ingrid M., Krdzalic, Jasenko, Krielen, Pepijn, Kroese, Leonard F., Krul, Eveline J.T., Lahuis, Derk H.H., Lamme, Bas, van Landeghem, An A.G., Leijtens, Jeroen W.A., Leseman-Hoogenboom, Mathilde M., de Lijster, Manou S., Marsman, Martijn S., Martens, MilouH., Masselink, Ilse, van der Meij, Wout, Meijnen, Philip, Melenhorst, Jarno, de Mey, Dietrich J.L., Moelker-Galuzina, Julia, Morsink, Linda, Mulder, Erik J., Muller, Karin, Musters, Gijsbert D., Neijenhuis, Peter A., de Nes, Lindsey C.F., Nielen, M., van den Nieuwboer, Jan B.J., Nieuwenhuis, Jonanne F., Nonner, Joost, Noordman, Bo J., Nordkamp, Stefi, Olthof, Pim B., Oosterling, Steven J., Ootes, Daan, Oppedijk, Vera, Ott, Pieter, Paulusma, Ida, Peeters, Koen C.M.J., Pereboom, Ilona T.A., Peringa, Jan, Pironet, Zoë, Plate, Joost D.J., Polat, Fatih, Poodt, Ingrid G.M., Posma, Lisanne A.E., Prette, Jeroen F., Pultrum, Bareld B., Qaderi, Seyed M., van Rees, Jan M., Renger, Rutger-Jan, Rombouts, Anouk J.M., Roosen, Lodewijk J., Roskott-ten Brinke, Ellen A., Rothbarth, Joost, Rouw, Dennis B., Rozema, Tom, Rütten, Heidi, Rutten, Harm J.T., van der Sande, Marit E., Schaafsma, Boudewijn E., Schasfoort, Renske A., Scheurkogel, Merel M., Schouten van der Velden, Arjan P., Schreurs, Wilhelmina H., Schuivens, Puck M.E., Sietses, Colin, Simons, Petra C.G., Slob, Marjan J., Slooter, Gerrit D., van der Sluis, Martsje, Smalbroek, Bo P., Smits, Anke B., Spillenaar-Bilgen, Ernst J., Spruit, Patty H., Stam, Tanja C., Stoker, Jaap, Talsma, Aaldert K., Temmink, Sofieke J.D., The, G.Y. Mireille, Tielbeek, Jeroen A.W., van Tilborg, Aukje A.J.M., van Tilborg, Fiek, van Trier, Dorothée, Tuynman, Jurriaan B., van der Valk, Maxime J.M., Vanhooymissen, Inge J.S., Vasbinder, G. Boudewijn C., Veeken, Cornelis J., Velema, Laura A., van de Ven, Anthony W.H., Verdaasdonk, Emiel G.G., Verduin, Wouter M., Verhagen, Tim, Verheijen, Paul M., Vermaas, Maarten, Verrijssen, An-Sofie E., Verschuur, Anna V.D., Schaik, Harmke Verwoerd-van, Vliegen, Roy F.A., Voets, Sophie, Vogelaar, F. Jeroen, Vogelij, Clementine L.A., Vos-Westerman, Johanna, de Vries, Marianne, Vroemen, Joy C., van Vugt, Bas S.T., Wegdam, Johannes A., van Wely, Bob J., Westerterp, Marinke, van Westerveld, Paul P., van Westreenen, Henderik L., Wijma, Allard G., de Wilt, Johannes H.W., de Wit, Bart W.K., Wit, Fennie, Woensdregt, Karlijn, van Woerden, Victor, van der Wolf, Floor S.W., van der Wolk, Sander, Wybenga, Johannes M., van der Zaag, Edwin S., Zamaray, Bobby, Zandvoort, Herman J.A., van der Zee, Dennis, Zeilstra, Annette P., Zheng, Kang J., Zimmerman, David D.E., Zorgdrager, Marcel, Geffen, Eline G.M. van, Nederend, Joost, Sluckin, Tania C., Hazen, Sanne-Marije J.A., Horsthuis, Karin, Beets-Tan, Regina G.H., Marijnen, Corrie A.M., Tanis, Pieter J., and Kusters, Miranda

Published
2024
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10. Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting

Author

Sluckin, Tania C., Hazen, Sanne-Marije J. A., Horsthuis, Karin, Beets-Tan, Regina G. H., Aalbers, Arend G. J., Beets, Geerard L., Boerma, Evert-Jan G., Borstlap, Jaap, van Breest Smallenburg, Vivian, Burger, Jacobus W. A., Crolla, Rogier M. P. H., Daniëls-Gooszen, Alette W., Davids, Paul H. P., Dunker, Michalda S., Fabry, Hans F. J., Furnée, Edgar J. B., van Gils, Renza A. H., de Haas, Robbert J., Hoogendoorn, Stefan, van Koeverden, Sebastiaan, de Korte, Fleur I., Oosterling, Steven J., Peeters, Koen C. M. J., Posma, Lisanne A. E., Pultrum, Bareld B., Rothbarth, Joost, Rutten, Harm J. T., Schasfoort, Renske A., Schreurs, Wilhelmina H., Simons, Petra C. G., Smits, Anke B., Talsma, Aaldert K., The, G. Y. Mireille, van Tilborg, Fiek, Tuynman, Jurriaan B., Vanhooymissen, Inge J. S., van de Ven, Anthony W. H., Verdaasdonk, Emiel G. G., Vermaas, Maarten, Vliegen, Roy F. A., Vogelaar, F. Jeroen, de Vries, Marianne, Vroemen, Joy C., van Vugt, Sebastiaan T., Westerterp, Marinke, van Westreenen, Henderik L., de Wilt, Johannes H. W., van der Zaag, Edwin S., Zimmerman, David D. E., Marijnen, Corrie A. M., Tanis, Pieter J., and Kusters, Miranda

Published
2023
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13. ASO Visual Abstract: Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting

Author

Sluckin, Tania C., Hazen, Sanne-Marije J. A., Horsthuis, Karin, Beets-Tan, Regina G. H., Aalbers, Arend G. J., Beets, Geerard L., Boerma, Evert-Jan G., Borstlap, Jaap, van Breest Smallenburg, Vivian, Burger, Jacobus W. A., Crolla, Rogier M. P. H., Daniëls-Gooszen, Alette W., Davids, Paul H. P., Dunker, Michalda S., Fabry, Hans F. J., Furnée, Edgar J. B., van Gils, Renza A. H., de Haas, Robbert J., Hoogendoorn, Stefan, van Koeverden, Sebastiaan, de Korte, Fleur I., Oosterling, Steven J., Peeters, Koen C. M. J., Posma, Lisanne A. E., Pultrum, Bareld B., Rothbarth, Joost, Rutten, Harm J. T., Schasfoort, Renske A., Schreurs, Wilhelmina H., Simons, Petra C. G., Smits, Anke B., Talsma, Aaldert K., The, G. Y. Mireille, van Tilborg, Fiek, Tuynman, Jurriaan B., Vanhooymissen, Inge J., van de Ven, Anthony W. H., Verdaasdonk, Emiel G. G., Vermaas, Maarten, Vliegen, Roy F. A., Vogelaar, F. Jeroen, de Vries, Marianne, Vroemen, Joy C., van Vugt, Sebastiaan T., Westerterp, Marinke, van Westreenen, Henderik L., de Wilt, Johannes H. W., van der Zaag, Edwin S., Zimmerman, David D. E., Marijnen, Corrie A. M., Tanis, Pieter J., and Kusters, Miranda

Published
2023
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14. Prediction of metastatic pheochromocytoma and paraganglioma: a machine learning modelling study using data from a cross-sectional cohort

Author

Pamporaki, Christina, Berends, Annika M A, Filippatos, Angelos, Prodanov, Tamara, Meuter, Leah, Prejbisz, Alexander, Beuschlein, Felix, Fassnacht, Martin, Timmers, Henri J L M, Nölting, Svenja, Abhyankar, Kaushik, Constantinescu, Georgiana, Kunath, Carola, de Haas, Robbert J, Wang, Katharina, Remde, Hanna, Bornstein, Stefan R, Januszewicz, Andrzeij, Robledo, Mercedes, Lenders, Jacques W M, Kerstens, Michiel N, Pacak, Karel, and Eisenhofer, Graeme

Published
2023
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16. SAT-474 Lesions hyper- to isointense to the surrounding liver in the hepatobiliary phase of gadoxetic acid enhanced MRI

Author

Furumaya, Alicia, primary, Willemssen, Francois, additional, Miclea, Razvan, additional, Haring, Martijn, additional, de Haas, Robbert, additional, Feshtali, Shirin, additional, Vanhooymissen, Inge, additional, Bos, Daniel, additional, de Man, Robert A., additional, Ijzermans, Jan, additional, Erdmann, Joris, additional, Verheij, Joanne, additional, Doukas, Michail, additional, van Delden, Otto, additional, and Thomeer, Maarten, additional

Published
2024
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17. Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial

Author

Blomjous, JG, de Boer, MT, van den Boezem, P, Bouwense, S, Bruijnen, R, Buis, CI, del Chiaro, M, Coene, PP, Coolsen, M, Daams, F, Dejong, K, Draaisma, W, Eker, HH, Elsen, AH, Gerhards, MF, Hartog, H, Hoogwater, FJ, Imani, F, Jenniskens, S, de Jong, KP, Karsten, TM, Klaase, JM, de Kleine, RHJ, van Laarhoven, CJ, van der Lelij, H, Manusama, ER, Meerdink, M, Meijerink, M, Nederend, J, Nijkamp, MW, Nota, CL, Porte, RJ, Reef, J, de Reuver, P, van Rijswijk, C, Romkens, T, Rupert, C, van der Schelling, GP, Serafino, JP, Vos, LD, Vriens, MR, Beers-Vural, E, Wagtenberg, JM, Wijsman, JH, de Wilde, RF, Wolfgang, CL, Zeh, HJ, III, Smits, F Jasmijn, Henry, Anne Claire, Besselink, Marc G, Busch, Olivier R, van Eijck, Casper H, Arntz, Mark, Bollen, Thomas L, van Delden, Otto M, van den Heuvel, Daniel, van der Leij, Christiaan, van Lienden, Krijn P, Moelker, Adriaan, Bonsing, Bert A, Borel Rinkes, Inne H, Bosscha, Koop, van Dam, Ronald M, Derksen, Wouter J M, den Dulk, Marcel, Festen, Sebastiaan, Groot Koerkamp, Bas, de Haas, Robbert J, Hagendoorn, Jeroen, van der Harst, Erwin, de Hingh, Ignace H, Kazemier, Geert, van der Kolk, Marion, Liem, Mike, Lips, Daan J, Luyer, Misha D, de Meijer, Vincent E, Mieog, J Sven, Nieuwenhuijs, Vincent B, Patijn, Gijs A, te Riele, Wouter W, Roos, Daphne, Schreinemakers, Jennifer M, Stommel, Martijn W J, Wit, Fennie, Zonderhuis, Babs A, Daamen, Lois A, van Werkhoven, C Henri, Molenaar, I Quintus, and van Santvoort, Hjalmar C

Published
2022
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18. Gallbladder reporting and data system (GB-RADS) for risk stratification of gallbladder wall thickening on ultrasonography: an international expert consensus

Author

Gupta, Pankaj, Dutta, Usha, Rana, Pratyaksha, Singhal, Manphool, Gulati, Ajay, Kalra, Naveen, Soundararajan, Raghuraman, Kalage, Daneshwari, Chhabra, Manika, Sharma, Vishal, Gupta, Vikas, Yadav, Thakur Deen, Kaman, Lileshwar, Irrinki, Santosh, Singh, Harjeet, Sakaray, Yashwant, Das, Chandan Krishuna, Saikia, Uma, Nada, Ritambhara, Srinivasan, Radhika, Sandhu, Manavjit Singh, Sharma, Raju, Shetty, Nitin, Eapen, Anu, Kaur, Harmeet, Kambadakone, Avinash, de Haas, Robbert, Kapoor, Vinay K., Barreto, Savio George, Sharma, Atul K., Patel, Amol, Garg, Pramod, Pal, Sujoy K., Goel, Mahesh, Patkar, Shraddha, Behari, Anu, Agarwal, Anil K., Sirohi, Bhawna, Javle, Milind, Garcea, Giuseppe, Nervi, Flavio, Adsay, Volkan, Roa, Juan Carlos, and Han, Ho-Seong

Published
2022
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21. Prognostic significance of MRI-detected extramural venous invasion according to grade and response to neo-adjuvant treatment in locally advanced rectal cancer A national cohort study after radiologic training and reassessment

Author

Geffen, Eline G.M. van, primary, Nederend, Joost, additional, Sluckin, Tania C., additional, Hazen, Sanne-Marije J.A., additional, Horsthuis, Karin, additional, Beets-Tan, Regina G.H., additional, Marijnen, Corrie A.M., additional, Tanis, Pieter J., additional, Kusters, Miranda, additional, Aalbers, Arend G.J., additional, van Aalten, Susanna M., additional, Amelung, Femke J., additional, Ankersmit, Marjolein, additional, Antonisse, Imogeen E., additional, Ashruf, Jesse F., additional, Aukema, Tjeerd S., additional, Avenarius, Henk, additional, Bahadoer, Renu R., additional, Bakers, Frans C.H., additional, Bakker, Ilsalien S., additional, Bangert, Fleur, additional, Barendse, Renée M., additional, Beekhuis, Heleen M.D., additional, Beets, Geerard L., additional, Bemelman, Willem A., additional, Berbée, Maaike, additional, de Bie, Shira H., additional, Bisschops, Robert H.C., additional, Blok, Robin D., additional, van Bockel, Liselotte W., additional, Boer, Anniek H., additional, den Boer, Frank C., additional, Boerma, Evert-Jan G., additional, Boogerd, Leonora S.F., additional, Borstlap, Jaap, additional, Borstlap, Wernard A.A., additional, Bouwman, Johanna E., additional, Braak, Sicco J., additional, Braat, Manon N.G.J.A., additional, Bradshaw, Jennifer, additional, Brandsma, Amarins T.A., additional, van Breest Smallenburg, Vivian, additional, van den Broek, Wim T., additional, van der Burg, Sjirk W., additional, Burger, Jacobus W.A., additional, Burghgraef, Thijs A., additional, ten Cate, David W.G., additional, Ceha, Heleen M., additional, Cnossen, Jeltsje S., additional, Coebergh van den Braak, Robert R.J., additional, Consten, Esther C.J., additional, Corver, Maaike, additional, Crolla, Rogier M.P.H., additional, Curutchet, Sam, additional, Daniëls-Gooszen, Alette W., additional, Davids, Paul H.P., additional, Dekker, Emmelie N., additional, Dekker, Jan Willem T., additional, Demirkiran, Ahmet, additional, Derksen, Tyche, additional, Diederik, Arjen L., additional, Dinaux, Anne M., additional, Dogan, Kemal, additional, van Dop, Ilse M., additional, Droogh-de Greve, Kitty E., additional, Duijsens, Hanneke M.H., additional, Dunker, Michalda S., additional, Duyck, Johan, additional, van Duyn, Eino B., additional, van Egdom, Laurentine S.E., additional, Eijlers, Bram, additional, El-Massoudi, Youssef, additional, van Elderen, Saskia, additional, Emmen, Anouk M.L.H., additional, Engelbrecht, Marc, additional, van Erp, Anne C., additional, van Essen, Jeroen A., additional, Fabry, Hans F.J., additional, Fassaert, Thomas, additional, Feitsma, Eline A., additional, Feshtali, Shirin S., additional, Frietman, Bas, additional, Furnée, Edgar J.B., additional, van Geel, Anne M., additional, Geijsen, Elisabeth D., additional, van Geloven, Anna A.W., additional, Gerhards, Michael F., additional, Gielkens, Hugo, additional, van Gils, Renza A.H., additional, Goense, Lucas, additional, Govaert, Marc J.P.M., additional, van Grevenstein, Wilhelmina M.U., additional, Joline de Groof, E., additional, de Groot, Irene, additional, de Haas, Robbert J., additional, Hakkenbrak, Nadia A.G., additional, den Hartogh, Mariska D., additional, Heesink, Vera, additional, Heikens, Joost T., additional, Hendriksen, Ellen M., additional, van den Hoek, Sjoerd, additional, van der Hoeven, Erik J.R.J., additional, Hoff, Christiaan, additional, Hogewoning, Anna, additional, Hogewoning, Cornelis R.C., additional, Hoogendoorn, Stefan, additional, van Hoorn, Francois, additional, van der Hul, René L., additional, van Hulst, Rieke, additional, Imani, Farshad, additional, Inberg, Bas, additional, Intven, Martijn P.W., additional, Janssen, Pedro, additional, de Jong, Chris E.J., additional, Jonkers, Jacoline, additional, Jou-Valencia, Daniela, additional, Keizers, Bas, additional, Ketelaers, Stijn H.J., additional, Knöps, Eva, additional, van Koeverden, Sebastiaan, additional, Kok, Sylvia, additional, Kolderman, Stephanie E.M., additional, de Korte, Fleur I., additional, Kortekaas, Robert T.J., additional, Korving, Julie C., additional, Koster, Ingrid M., additional, Krdzalic, Jasenko, additional, Krielen, Pepijn, additional, Kroese, Leonard F., additional, Krul, Eveline J.T., additional, Lahuis, Derk H.H., additional, Lamme, Bas, additional, van Landeghem, An A.G., additional, Leijtens, Jeroen W.A., additional, Leseman-Hoogenboom, Mathilde M., additional, de Lijster, Manou S., additional, Marsman, Martijn S., additional, Martens, MilouH., additional, Masselink, Ilse, additional, van der Meij, Wout, additional, Meijnen, Philip, additional, Melenhorst, Jarno, additional, de Mey, Dietrich J.L., additional, Moelker-Galuzina, Julia, additional, Morsink, Linda, additional, Mulder, Erik J., additional, Muller, Karin, additional, Musters, Gijsbert D., additional, Neijenhuis, Peter A., additional, de Nes, Lindsey C.F., additional, Nielen, M., additional, van den Nieuwboer, Jan B.J., additional, Nieuwenhuis, Jonanne F., additional, Nonner, Joost, additional, Noordman, Bo J., additional, Nordkamp, Stefi, additional, Olthof, Pim B., additional, Oosterling, Steven J., additional, Ootes, Daan, additional, Oppedijk, Vera, additional, Ott, Pieter, additional, Paulusma, Ida, additional, Peeters, Koen C.M.J., additional, Pereboom, Ilona T.A., additional, Peringa, Jan, additional, Pironet, Zoë, additional, Plate, Joost D.J., additional, Polat, Fatih, additional, Poodt, Ingrid G.M., additional, Posma, Lisanne A.E., additional, Prette, Jeroen F., additional, Pultrum, Bareld B., additional, Qaderi, Seyed M., additional, van Rees, Jan M., additional, Renger, Rutger-Jan, additional, Rombouts, Anouk J.M., additional, Roosen, Lodewijk J., additional, Roskott-ten Brinke, Ellen A., additional, Rothbarth, Joost, additional, Rouw, Dennis B., additional, Rozema, Tom, additional, Rütten, Heidi, additional, Rutten, Harm J.T., additional, van der Sande, Marit E., additional, Schaafsma, Boudewijn E., additional, Schasfoort, Renske A., additional, Scheurkogel, Merel M., additional, Schouten van der Velden, Arjan P., additional, Schreurs, Wilhelmina H., additional, Schuivens, Puck M.E., additional, Sietses, Colin, additional, Simons, Petra C.G., additional, Slob, Marjan J., additional, Slooter, Gerrit D., additional, van der Sluis, Martsje, additional, Smalbroek, Bo P., additional, Smits, Anke B., additional, Spillenaar-Bilgen, Ernst J., additional, Spruit, Patty H., additional, Stam, Tanja C., additional, Stoker, Jaap, additional, Talsma, Aaldert K., additional, Temmink, Sofieke J.D., additional, The, G.Y. Mireille, additional, Tielbeek, Jeroen A.W., additional, van Tilborg, Aukje A.J.M., additional, van Tilborg, Fiek, additional, van Trier, Dorothée, additional, Tuynman, Jurriaan B., additional, van der Valk, Maxime J.M., additional, Vanhooymissen, Inge J.S., additional, Vasbinder, G. Boudewijn C., additional, Veeken, Cornelis J., additional, Velema, Laura A., additional, van de Ven, Anthony W.H., additional, Verdaasdonk, Emiel G.G., additional, Verduin, Wouter M., additional, Verhagen, Tim, additional, Verheijen, Paul M., additional, Vermaas, Maarten, additional, Verrijssen, An-Sofie E., additional, Verschuur, Anna V.D., additional, Schaik, Harmke Verwoerd-van, additional, Vliegen, Roy F.A., additional, Voets, Sophie, additional, Vogelaar, F. Jeroen, additional, Vogelij, Clementine L.A., additional, Vos-Westerman, Johanna, additional, de Vries, Marianne, additional, Vroemen, Joy C., additional, van Vugt, Bas S.T., additional, Wegdam, Johannes A., additional, van Wely, Bob J., additional, Westerterp, Marinke, additional, van Westerveld, Paul P., additional, van Westreenen, Henderik L., additional, Wijma, Allard G., additional, de Wilt, Johannes H.W., additional, de Wit, Bart W.K., additional, Wit, Fennie, additional, Woensdregt, Karlijn, additional, van Woerden, Victor, additional, van der Wolf, Floor S.W., additional, van der Wolk, Sander, additional, Wybenga, Johannes M., additional, van der Zaag, Edwin S., additional, Zamaray, Bobby, additional, Zandvoort, Herman J.A., additional, van der Zee, Dennis, additional, Zeilstra, Annette P., additional, Zheng, Kang J., additional, Zimmerman, David D.E., additional, and Zorgdrager, Marcel, additional

Published
2024
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24. Improved ice-binding proteins based on twist constrained helices

Author

De Haas, Robbert Jan, de Vries, Rindert Jakob, Tas, Roderick, Voets, Ilja, De Haas, Robbert Jan, de Vries, Rindert Jakob, Tas, Roderick, and Voets, Ilja

Abstract

The invention relates to a protein comprising at least one ice-binding alpha helix, wherein the ice-binding helix has a twist of less than 100 degrees per residue, preferably a twist of less than 99 degrees per residue, most preferably a twist of about 98.2 degrees per residue. The invention further relates to a composition comprising such protein. The invention further relates to the use of said protein or composition as a cryopreservation agent, as a gas hydrate inhibitor or in coatings for de-icing materials. Lastly, the invention furthermore relates to a method for cryopreserving an aqueous mixture using said protein and a method for producing said protein.

Published
2024

27. Sonic hedgehog hepatocellular adenoma: magnetic resonance imaging features and correlation with histology

Author

Ducatel, Arnaud, primary, Trillaud, Hervé, additional, Reizine, Edouard, additional, Vilgrain, Valérie, additional, Sempoux, Christine, additional, Schmidt-Kobbe, Sabine, additional, Gouw, Annette S. H., additional, de Haas, Robbert J, additional, Julien, Céline, additional, Paradis, Valérie, additional, Blanc, Jean-Frédéric, additional, Chiche, Laurence, additional, Balabaud, Charles, additional, Bioulac-Sage, Paulette, additional, and Frulio, Nora, additional

Published
2023
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29. No need for fasting prior to doppler ultrasound of pediatric liver transplants: A self‐controlled study.

Author

Verhagen, Martijn V., van der Doef, Hubert P. J., Kwee, Thomas C., and de Haas, Robbert J.

Subjects
DOPPLER ultrasonography, LIVER transplantation, HEPATIC veins, HEPATIC artery, INTRACLASS correlation
Abstract

Background: Children frequently undergo routine Doppler‐ultrasound (DUS) after liver transplantation (LT) for which they are fasted, but this may cause hunger and discomfort. Objective: To determine if DUS measurements, with focus on the portal vein (PV), are affected by prandial changes, and if this affects distress and feasibility of the DUS. Materials and Methods: Children were prospectively included to undergo a pre‐ and postprandial DUS on the same day at 6 months after LT. Pre‐ and anastomotic PV peak systolic velocity (PSV), and hepatic artery and hepatic vein DUS measurements were obtained. Pre‐ and postprandial measurements, and relative postprandial change of PV velocity ratio (VR) compared to PV anastomotic PSV, were compared using paired‐sample t‐tests and intraclass correlation coefficients (ICC). Obscuration by bowel gas, difficulty of DUS, and impact of fasting were assessed using 5‐point rating scales. Results: Twenty‐eight children (median age 3.5 years, IQR 1.6–10.8) were included; four were subsequently excluded because they were not fasted (N = 2) or withdrew consent for the second DUS (N = 2). Measurements between pre‐ and postprandial DUS, and relative postprandial change of VR compared to PV anastomotic PSV, were not significantly different (p >.05). Test consistency was good (ICC = 0.69, 95% CI = 0.29–0.67) for PV anastomotic PSV, and excellent (95% CI = 0.61–0.93) for PV VR. Obscuration by bowel gas or ease of DUS did not change after eating (p >.05). The majority (16/28, 57.2%) found fasting difficult, and several (13/28, 46.4%) got upset when fasted. Conclusion: Children with an LT do not need to be fasted for routine DUS, which may decrease the burden of the examination. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Auto-segmentation of the residual pancreas after pancreatic resection

Author

Böhm, Dennis, primary, Andel, Paul, primary, Akkermans, Paul, primary, Boekestijn, Bas, primary, van der Geest, Willem, primary, de Haas, Robbert, primary, Intven, Martijn, primary, Kist, Jakob, primary, Nederend, Joost, primary, Pranger, Bobby, primary, Struik, Femke, primary, Verpalen, Inez, primary, Wessels, Frank, primary, Willemssen, François, primary, Zoetekouw, Ralf, primary, Dijkstra, Jouke, primary, Weinmann, Michael, primary, and Daamen, Lois, primary

Published
2023
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34. Rapid and automated design of two-component protein nanomaterials using ProteinMPNN

Author

de Haas, Robbert J., primary, Brunette, Natalie, additional, Goodson, Alex, additional, Dauparas, Justas, additional, Yi, Sue Y., additional, Yang, Erin C., additional, Dowling, Quinton, additional, Nguyen, Hannah, additional, Kang, Alex, additional, Bera, Asim K., additional, Sankaran, Banumathi, additional, de Vries, Renko, additional, Baker, David, additional, and King, Neil P., additional

Published
2023
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37. Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST

Author

de Mestier, Louis, primary, Resche‐Rigon, Matthieu, additional, Dromain, Clarisse, additional, Lamarca, Angela, additional, La Salvia, Anna, additional, de Baker, Lesley, additional, Fehrenbach, Uli, additional, Pusceddu, Sara, additional, Colao, Annamaria, additional, Borbath, Ivan, additional, de Haas, Robbert, additional, Rinzivillo, Maria, additional, Zerbi, Alessandro, additional, Funicelli, Luigi, additional, de Herder, Wouter W., additional, Selberherr, Andreas, additional, Wagner, Anna Dorothea, additional, Manoharan, Prakash, additional, De Cima, Andrea, additional, Lybaert, Willem, additional, Jann, Henning, additional, Prinzi, Natalie, additional, Faggiano, Antongiulio, additional, Annet, Laurence, additional, Walenkamp, Annemiek, additional, Panzuto, Francesco, additional, Pedicini, Vittorio, additional, Pitoni, Maria Giovanna, additional, Siebenhuener, Alexander, additional, Mayerhoefer, Marius E., additional, Ruszniewski, Philippe, additional, and Vullierme, Marie‐Pierre, additional

Published
2023
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40. Variation in the management of benign liver tumors: A European survey and case vignette study

Author

Haring, Martijn P.D., primary, de Haas, Robbert J., additional, van Vilsteren, Frederike G.I., additional, Klaase, Joost M., additional, Duiker, Evelien W., additional, Blokzijl, Hans, additional, de Jong, Koert P., additional, de Meijer, Vincent E., additional, Cuperus, Frans J.C., additional, de Boer, Y.S., additional, de Man, R.A., additional, den Hoed, C.M., additional, Drenth, J.P.H., additional, Garcovich, M.G., additional, Gevers, T.J.G., additional, Klompenhouwer, A.J., additional, Kramer, M., additional, Tushuizen, M.E., additional, van der Meer, A.J., additional, Burgmans, M.C., additional, Cannella, R.C., additional, Caseiro-Alves, F.C., additional, Denecke, T.D., additional, Dwarkasing, R.S., additional, Fehrenbach, U.F., additional, Feshtali, S., additional, Miclea, R.L., additional, Poyanli, A.P., additional, Ronot, M.R., additional, Sartoris, R.S., additional, Thomeer, Maarten, additional, van der Leij, C., additional, van Koeverden, S.K., additional, Vermersch, M.V., additional, Vernuccio, F.V., additional, Willemssen, F.E.J.A., additional, Addeo, P.A., additional, Alexandrino, H., additional, Belli, A., additional, Bemelmans, M.H.A., additional, Boleslawski, E.B., additional, Coelen, R.J.S., additional, de Boer, M.T., additional, de Kleine, R.H., additional, den Dulk, M., additional, Frilling, A.F., additional, Furumaya, A., additional, Irinel, I.P., additional, Regimbeau, J.M., additional, Manuela, M.C., additional, Özden, İ., additional, Sallinen, V.S., additional, Schaapherder, A.F., additional, Schmelzle, M.S., additional, Seehofer, D., additional, Trotovšek, B., additional, Truant, S.T., additional, van den Boezem, P.B., additional, and van Rosmalen, B.V., additional

Published
2023
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43. A dual-tracer approach using [11C]CH and [18F]FDG in HCC clinical decision making

Author

Veenstra, E, Ruiter, S, de Haas, R, de Jong, K, Erba, P, Dierckx, R, Noordzij, W, Veenstra, Emile B, Ruiter, Simeon J S, de Haas, Robbert J, de Jong, Koert P, Erba, Paola A, Dierckx, Rudi A J O, Noordzij, Walter, Veenstra, E, Ruiter, S, de Haas, R, de Jong, K, Erba, P, Dierckx, R, Noordzij, W, Veenstra, Emile B, Ruiter, Simeon J S, de Haas, Robbert J, de Jong, Koert P, Erba, Paola A, Dierckx, Rudi A J O, and Noordzij, Walter

Abstract

Background: Early detection of recurrent or progressive HCC remains the strongest prognostic factor for survival. Dual tracer PET/CT imaging with [11C]CH and [18F]FDG can further increase detection rates as both tracers entail different metabolic pathways involved in HCC development. We investigated dual-tracer PET/CT in clinical decision making in patients suspected of recurrent or progressive HCC. All HCC patients who underwent both [11C]CH and [18F]FDG PET/CT in our institute from February 2018 to December 2021 were included. Both tracer PET/CT were within 4 weeks of each other with at least 6-month follow-up. Patients underwent dual tracer PET/CT because of unexplained and suspicious CT/MRI or sudden rise of serum tumour markers. A detected lesion was considered critical when the finding had prognostic consequences leading to treatment changes. Results: Nineteen patients who underwent [11C]CH and [18F]FDG PET/CT were included of which all but six patients were previously treated for HCC. Dual-tracer critical finding detection rate was 95%, with [18F]FDG 68%, and [11C]CH 84%. Intrahepatic HCC recurrence finding rate was 65% for both tracers. [18F]FDG found more ablation site recurrences (4/5) compared to [11C]CH (2/5). Only [11C]CH found two needle tract metastases. Both tracers found 75% of the positive lymph nodes. Two new primary tumours were found, one by [18F]FDG and both by [11C]CH. Conclusions: Our study favours a dual-tracer approach in HCC staging in high-risk patients or when conventional imaging is non-conclusive.

Published
2023

44. Modular Design for Proteins Assembling into Antifouling Coatings : Case of Gold Surfaces

Author

Zheng, Chuanbao, Alvisi, Nicolò, de Haas, Robbert Jan, Zhang, Zhisen, Zuilhof, Han, de Vries, Renko, Zheng, Chuanbao, Alvisi, Nicolò, de Haas, Robbert Jan, Zhang, Zhisen, Zuilhof, Han, and de Vries, Renko

Abstract

We analyze modularity for a B-M-E triblock protein designed to self-assemble into antifouling coatings. Previously, we have shown that the design performs well on silica surfaces when B is taken to be a silica-binding peptide, M is a thermostable trimer domain, and E is the uncharged elastin-like polypeptide (ELP), E = (GSGVP)40. Here, we demonstrate that we can modulate the nature of the substrate on which the coatings form by choosing different solid-binding peptides as binding domain B and that we can modulate antifouling properties by choosing a different hydrophilic block E. Specifically, to arrive at antifouling coatings for gold surfaces, as binding block B we use the gold-binding peptide GBP1 (with the sequence MHGKTQATSGTIQS), while we replace the antifouling blocks E by zwitterionic ELPs of different lengths, EZn = (GDGVP-GKGVP)n/2, with n = 20, 40, or 80. We find that even the B-M-E proteins with the shortest E blocks make coatings on gold surfaces with excellent antifouling against 1% human serum (HS) and reasonable antifouling against 10% HS. This suggests that the B-M-E triblock protein can be easily adapted to form antifouling coatings on any substrate for which solid-binding peptide sequences are available.

Published
2023

45. De novo designed ice-binding proteins from twist-constrained helices

Author

de Haas, Robbert J., Tas, Roderick P., van den Broek, Daniëlle, Zheng, Chuanbao, Nguyen, Hannah, Kang, Alex, Bera, Asim K., King, Neil P., Voets, Ilja K., de Vries, Renko, de Haas, Robbert J., Tas, Roderick P., van den Broek, Daniëlle, Zheng, Chuanbao, Nguyen, Hannah, Kang, Alex, Bera, Asim K., King, Neil P., Voets, Ilja K., and de Vries, Renko

Abstract

Attaining molecular-level control over solidification processes is a crucial aspect of materials science. To control ice formation, organisms have evolved bewildering arrays of ice-binding proteins (IBPs), but these have poorly understood structure–activity relationships. We propose that reverse engineering using de novo computational protein design can shed light on structure–activity relationships of IBPs. We hypothesized that the model alpha-helical winter flounder antifreeze protein uses an unusual undertwisting of its alpha-helix to align its putative ice-binding threonine residues in exactly the same direction. We test this hypothesis by designing a series of straight three-helix bundles with an ice-binding helix projecting threonines and two supporting helices constraining the twist of the ice-binding helix. Our findings show that ice-recrystallization inhibition by the designed proteins increases with the degree of designed undertwisting, thus validating our hypothesis, and opening up avenues for the computational design of IBPs.

Published
2023

46. Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors:Alternatives to RECIST

Author

de Mestier, Louis, Resche-Rigon, Matthieu, Dromain, Clarisse, Lamarca, Angela, La Salvia, Anna, de Baker, Lesley, Fehrenbach, Uli, Pusceddu, Sara, Colao, Annamaria, Borbath, Ivan, de Haas, Robbert, Rinzivillo, Maria, Zerbi, Alessandro, Funicelli, Luigi, de Herder, Wouter W., Selberherr, Andreas, Wagner, Anna Dorothea, Manoharan, Prakash, De Cima, Andrea, Lybaert, Willem, Jann, Henning, Prinzi, Natalie, Faggiano, Antongiulio, Annet, Laurence, Walenkamp, Annemiek, Panzuto, Francesco, Pedicini, Vittorio, Pitoni, Maria Giovanna, Siebenhuener, Alexander, Mayerhoefer, Marius E., Ruszniewski, Philippe, Vullierme, Marie Pierre, de Mestier, Louis, Resche-Rigon, Matthieu, Dromain, Clarisse, Lamarca, Angela, La Salvia, Anna, de Baker, Lesley, Fehrenbach, Uli, Pusceddu, Sara, Colao, Annamaria, Borbath, Ivan, de Haas, Robbert, Rinzivillo, Maria, Zerbi, Alessandro, Funicelli, Luigi, de Herder, Wouter W., Selberherr, Andreas, Wagner, Anna Dorothea, Manoharan, Prakash, De Cima, Andrea, Lybaert, Willem, Jann, Henning, Prinzi, Natalie, Faggiano, Antongiulio, Annet, Laurence, Walenkamp, Annemiek, Panzuto, Francesco, Pedicini, Vittorio, Pitoni, Maria Giovanna, Siebenhuener, Alexander, Mayerhoefer, Marius E., Ruszniewski, Philippe, and Vullierme, Marie Pierre

Abstract

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06–3.40; p =.03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p =.91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment

Published
2023

47. A nationwide assessment of hepatocellular adenoma resection:Indications and pathological discordance

Author

Haring, Martijn P D, Elfrink, Arthur K E, Oudmaijer, Christiaan A J, Andel, Paul C M, Furumaya, Alicia, de Jong, Nenke, Willems, Colin J J M, Huits, Thijs, Sijmons, Julie M L, Belt, Eric J T, Bosscha, Koop, Consten, Esther C J, Coolsen, Mariëlle M E, van Duijvendijk, Peter, Erdmann, Joris I, Gobardhan, Paul, de Haas, Robbert J, van Heek, Tjarda, Lam, Hwai-Ding, Leclercq, Wouter K G, Liem, Mike S L, Marsman, Hendrik A, Patijn, Gijs A, Terkivatan, Türkan, Zonderhuis, Babs M, Molenaar, Izaak Quintus, Te Riele, Wouter W, Hagendoorn, Jeroen, Schaapherder, Alexander F M, IJzermans, Jan N M, Buis, Carlijn I, Klaase, Joost M, de Jong, Koert P, de Meijer, Vincent E, Haring, Martijn P D, Elfrink, Arthur K E, Oudmaijer, Christiaan A J, Andel, Paul C M, Furumaya, Alicia, de Jong, Nenke, Willems, Colin J J M, Huits, Thijs, Sijmons, Julie M L, Belt, Eric J T, Bosscha, Koop, Consten, Esther C J, Coolsen, Mariëlle M E, van Duijvendijk, Peter, Erdmann, Joris I, Gobardhan, Paul, de Haas, Robbert J, van Heek, Tjarda, Lam, Hwai-Ding, Leclercq, Wouter K G, Liem, Mike S L, Marsman, Hendrik A, Patijn, Gijs A, Terkivatan, Türkan, Zonderhuis, Babs M, Molenaar, Izaak Quintus, Te Riele, Wouter W, Hagendoorn, Jeroen, Schaapherder, Alexander F M, IJzermans, Jan N M, Buis, Carlijn I, Klaase, Joost M, de Jong, Koert P, and de Meijer, Vincent E

Abstract

Hepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of patients operated for HCAs < 50 mm compared to HCAs ≥ 50 mm. Changes in final postoperative diagnosis were assessed. We performed a retrospective study that included patients who underwent resection for (suspected) HCAs in the Netherlands from 2014 to 2019. Indication for resection was analyzed and stratified for small (<50 mm) and large (≥50 mm) tumors. Logistic regression analysis was performed on factors influencing change in tumor diagnosis. Out of 222 patients who underwent surgery, 44 (20%) patients had a tumor <50 mm. Median age was 46 (interquartile range [IQR], 33-56) years in patients with small tumors and 37 (IQR, 31-46) years in patients with large tumors (p = 0.016). Patients with small tumors were more frequently men (21% vs. 5%, p = 0.002). Main indications for resection in patients with small tumors were suspicion of (pre)malignancy (55%), (previous) bleeding (14%), and male sex (11%). Patients with large tumors received operations because of tumor size >50 mm (52%), suspicion of (pre)malignancy (28%), and (previous) bleeding (5.1%). No difference was observed in HCA-subtype distribution between small and large tumors. Ninety-six (43%) patients had a postoperative change in diagnosis. Independent risk factors for change in diagnosis were tumor size <50 mm (adjusted odds ratio [aOR], 3.4; p < 0.01), male sex (aOR, 3.7; p = 0.03), and lack of hepatobiliary contrast-enhanced magnetic resonance imaging (CE-MRI) (aOR, 1.8; p = 0.04). Resection for small (suspected) HCAs was mainly indicated by suspicion of (pre)malignancy, whereas for large (suspected) HCAs, tumor size was the most prevalent indication. Male sex, tumor size <50 mm, and lack of hepatobiliary CE-MRI were independent risk factors for postoperative change in tumor diagnosis.

Published
2023

49. Multidisciplinary management of chronic refractory pain in autosomal dominant polycystic kidney disease

Author

van Luijk, Franka, Gansevoort, Ron T, Blokzijl, Hans, Groen, Gerbrand J, de Haas, Robbert J, Leliveld, Anna M, Meijer, Esther, Perdok, Joke M, Stellema, Ruud, Wolff, Andreas P, Casteleijn, Niek F, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), and Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE)

Subjects
Transplantation, Nephrology
Abstract

Background Chronic pain is often difficult to manage in autosomal dominant polycystic kidney disease (ADPKD) patients and sometimes even leads to nephrectomy. We analyzed the long-term efficacy of our innovative multidisciplinary protocol to treat chronic refractory pain that aims to preserve kidney function by applying among other sequential nerve blocks. Methods Patients were eligible if pain was present ≥3 months with a score of ≥50 on a visual analog scale (VAS) of 100, was negatively affecting quality of life and if there had been insufficient response to previous therapies, including opioid treatment. Treatment options were, in order, analgesics, cyst aspiration and fenestration, nerve blocks and nephrectomy. Results A total of 101 patients were assessed in our clinic (mean age 50 ± 11 years, 65.3% females). Eight patients were treated with medication, 6 by cyst aspiration or fenestration, 63 by nerve blocks and 6 received surgery as the first treatment option. Overall, 76.9% experienced a positive effect on pain complaints shortly after treatment. The VAS score was reduced from 60/100 to 20/100 (P Conclusions These data indicate that our multidisciplinary treatment protocol appears effective in reducing pain in the majority of patients with chronic refractory pain, while postponing or even avoiding in most patients surgical interventions such as nephrectomy in most patients.

Published
2023

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