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1. Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors – a genome-wide association study: results from PanCareLIFE

Author

van der Perk, M.E. Madeleine, Broer, Linda, Yasui, Yutaka, Laven, Joop S.E., Robison, Leslie L., Tissing, Wim J.E., Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J.L., Lambalk, Cornelis B., Overbeek, Annelies, Loonen, Jacqueline J., Beerendonk, Catharina C.M., Byrne, Julianne, Berger, Claire, Clemens, Eva, van Dulmen-den Broeder, Eline, Dirksen, Uta, van der Pal, Helena J., de Vries, Andrica C.H., Winther, Jeanette Falck, Ranft, Andreas, Fosså, Sophie D., Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Kremer, Leontien C.M., Brooke, Russell J., Wang, Fan, Baedke, Jessica L., Uitterlinden, André G., Bos, Annelies M.E., van Leeuwen, Flora E., Ness, Kirsten K., Hudson, Melissa M., van der Kooi, Anne-Lotte L.F., and van den Heuvel-Eibrink, Marry M.

Published
2024
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2. A comparison of genotyping arrays

Author

Verlouw, Joost A. M., Clemens, Eva, de Vries, Jard H., Zolk, Oliver, Verkerk, Annemieke J. M. H., am Zehnhoff-Dinnesen, Antoinette, Medina-Gomez, Carolina, Lanvers-Kaminsky, Claudia, Rivadeneira, Fernando, Langer, Thorsten, van Meurs, Joyce B. J., van den Heuvel-Eibrink, Marry M., Uitterlinden, André G., and Broer, Linda

Published
2021
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3. Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study

Author

Langer, Thorsten, Clemens, Eva, Broer, Linda, Maier, Lara, Uitterlinden, André G., de Vries, Andrica C.H., van Grotel, Martine, Pluijm, Saskia F.M., Binder, Harald, Mayer, Benjamin, von dem Knesebeck, Annika, Byrne, Julianne, van Dulmen-den Broeder, Eline, Crocco, Marco, Grabow, Desiree, Kaatsch, Peter, Kaiser, Melanie, Spix, Claudia, Kenborg, Line, Winther, Jeanette F., Rechnitzer, Catherine, Hasle, Henrik, Kepak, Tomas, van der Kooi, Anne-Lotte F., Kremer, Leontien C., Kruseova, Jarmila, Bielack, Stefan, Sorg, Benjamin, Hecker-Nolting, Stefanie, Kuehni, Claudia E., Ansari, Marc, Kompis, Martin, van der Pal, Heleen, Parfitt, Ross, Deuster, Dirk, Matulat, Peter, Tillmanns, Amelie, Tissing, Wim J.E., Beck, Jörn D., Elsner, Susanne, am Zehnhoff-Dinnesen, Antoinette, van den Heuvel-Eibrink, Marry M., and Zolk, Oliver

Published
2020
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4. The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients: A report from the PanCareLIFE consortium

Author

Zorg en O&O, Cancer, Child Health, Speerpunt, Scobioala, Sergiu, Parfitt, Ross, Matulat, Peter, Byrne, Julianne, Langer, Thorsten, Troschel, Fabian M., Hesping, Amélie E., Clemens, Eva, Kaatsch, Peter, Grabow, Desiree, Kaiser, Melanie, Spix, Claudia, Kremer, Leontien C., Calaminus, Gabriele, Baust, Katja, Kuehni, Claudia E., Weiss, Annette, Strebel, Sven, Kuonen, Rahel, Elsner, Susanne, Haupt, Riccardo, Garré, Maria Luisa, Gruhn, Bernd, Kepak, Tomas, Kepakova, Katerina, Winther, Jeanette Falck, Kenborg, Line, Rechnitzer, Catherine, Hasle, Henrik, Kruseova, Jarmila, Luks, Ales, Lackner, Herwig, Bielack, Stefan, Beck, Jörn Dirk, Jürgens, Heribert, van den Heuvel-Eibrink, Marry M., Zolk, Oliver, Eich, Hans Theodor, am Zehnhoff-Dinnesen, Antoinette, Zorg en O&O, Cancer, Child Health, Speerpunt, Scobioala, Sergiu, Parfitt, Ross, Matulat, Peter, Byrne, Julianne, Langer, Thorsten, Troschel, Fabian M., Hesping, Amélie E., Clemens, Eva, Kaatsch, Peter, Grabow, Desiree, Kaiser, Melanie, Spix, Claudia, Kremer, Leontien C., Calaminus, Gabriele, Baust, Katja, Kuehni, Claudia E., Weiss, Annette, Strebel, Sven, Kuonen, Rahel, Elsner, Susanne, Haupt, Riccardo, Garré, Maria Luisa, Gruhn, Bernd, Kepak, Tomas, Kepakova, Katerina, Winther, Jeanette Falck, Kenborg, Line, Rechnitzer, Catherine, Hasle, Henrik, Kruseova, Jarmila, Luks, Ales, Lackner, Herwig, Bielack, Stefan, Beck, Jörn Dirk, Jürgens, Heribert, van den Heuvel-Eibrink, Marry M., Zolk, Oliver, Eich, Hans Theodor, and am Zehnhoff-Dinnesen, Antoinette

Published
2024

5. Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE

Author

MS VPG/Gynaecologie, Cancer, Speerpunt, Zorg en O&O, Child Health, van der Perk, M E Madeleine, Broer, Linda, Yasui, Yutaka, Laven, Joop S E, Robison, Leslie L, Tissing, Wim J E, Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J L, Lambalk, Cornelis B, Overbeek, Annelies, Loonen, Jacqueline J, Beerendonk, Catharina C M, Byrne, Julianne, Berger, Claire, Clemens, Eva, van Dulmen-den Broeder, Eline, Dirksen, Uta, van der Pal, Helena J, de Vries, Andrica C H, Winther, Jeanette Falck, Ranft, Andreas, Fosså, Sophie D, Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Kremer, Leontien C M, Brooke, Russell J, Wang, Fan, Baedke, Jessica L, Uitterlinden, André G, Bos, Annelies M E, van Leeuwen, Flora E, Ness, Kirsten K, Hudson, Melissa M, van der Kooi, Anne-Lotte L F, van den Heuvel-Eibrink, Marry M, PanCareLIFE Consortium, MS VPG/Gynaecologie, Cancer, Speerpunt, Zorg en O&O, Child Health, van der Perk, M E Madeleine, Broer, Linda, Yasui, Yutaka, Laven, Joop S E, Robison, Leslie L, Tissing, Wim J E, Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J L, Lambalk, Cornelis B, Overbeek, Annelies, Loonen, Jacqueline J, Beerendonk, Catharina C M, Byrne, Julianne, Berger, Claire, Clemens, Eva, van Dulmen-den Broeder, Eline, Dirksen, Uta, van der Pal, Helena J, de Vries, Andrica C H, Winther, Jeanette Falck, Ranft, Andreas, Fosså, Sophie D, Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Kremer, Leontien C M, Brooke, Russell J, Wang, Fan, Baedke, Jessica L, Uitterlinden, André G, Bos, Annelies M E, van Leeuwen, Flora E, Ness, Kirsten K, Hudson, Melissa M, van der Kooi, Anne-Lotte L F, van den Heuvel-Eibrink, Marry M, and PanCareLIFE Consortium

Published
2024

6. Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors – a genome-wide association study:results from PanCareLIFE

Author

van der Perk, M. E.Madeleine, Broer, Linda, Yasui, Yutaka, Laven, Joop S.E., Robison, Leslie L., Tissing, Wim J.E., Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J.L., Lambalk, Cornelis B., Overbeek, Annelies, Loonen, Jacqueline J., Beerendonk, Catharina C.M., Byrne, Julianne, Berger, Claire, Clemens, Eva, van Dulmen-den Broeder, Eline, Dirksen, Uta, van der Pal, Helena J., de Vries, Andrica C.H., Winther, Jeanette Falck, Ranft, Andreas, Fosså, Sophie D., Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Kremer, Leontien C.M., Brooke, Russell J., Wang, Fan, Baedke, Jessica L., Uitterlinden, André G., Bos, Annelies M.E., van Leeuwen, Flora E., Ness, Kirsten K., Hudson, Melissa M., van der Kooi, Anne Lotte L.F., van den Heuvel-Eibrink, Marry M., van der Perk, M. E.Madeleine, Broer, Linda, Yasui, Yutaka, Laven, Joop S.E., Robison, Leslie L., Tissing, Wim J.E., Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J.L., Lambalk, Cornelis B., Overbeek, Annelies, Loonen, Jacqueline J., Beerendonk, Catharina C.M., Byrne, Julianne, Berger, Claire, Clemens, Eva, van Dulmen-den Broeder, Eline, Dirksen, Uta, van der Pal, Helena J., de Vries, Andrica C.H., Winther, Jeanette Falck, Ranft, Andreas, Fosså, Sophie D., Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Kremer, Leontien C.M., Brooke, Russell J., Wang, Fan, Baedke, Jessica L., Uitterlinden, André G., Bos, Annelies M.E., van Leeuwen, Flora E., Ness, Kirsten K., Hudson, Melissa M., van der Kooi, Anne Lotte L.F., and van den Heuvel-Eibrink, Marry M.

Abstract

Objective: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. Design: Genome-wide association study. Setting: Not applicable. Patients: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). Exposure: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. Results: Three genome-wide significant (<5.0 × 10−8) and 16 genome-wide suggestive (<5.0 × 10−6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): −0.484 (0.091). Con

Published
2024

7. The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients:A report from the PanCareLIFE consortium

Author

Scobioala, Sergiu, Parfitt, Ross, Matulat, Peter, Byrne, Julianne, Langer, Thorsten, Troschel, Fabian M., Hesping, Amélie E., Clemens, Eva, Kaatsch, Peter, Grabow, Desiree, Kaiser, Melanie, Spix, Claudia, Kremer, Leontien C., Calaminus, Gabriele, Baust, Katja, Kuehni, Claudia E., Weiss, Annette, Strebel, Sven, Kuonen, Rahel, Elsner, Susanne, Haupt, Riccardo, Garré, Maria Luisa, Gruhn, Bernd, Kepak, Tomas, Kepakova, Katerina, Winther, Jeanette Falck, Kenborg, Line, Rechnitzer, Catherine, Hasle, Henrik, Kruseova, Jarmila, Luks, Ales, Lackner, Herwig, Bielack, Stefan, Beck, Jörn Dirk, Jürgens, Heribert, van den Heuvel-Eibrink, Marry M., Zolk, Oliver, Eich, Hans Theodor, am Zehnhoff-Dinnesen, Antoinette, Scobioala, Sergiu, Parfitt, Ross, Matulat, Peter, Byrne, Julianne, Langer, Thorsten, Troschel, Fabian M., Hesping, Amélie E., Clemens, Eva, Kaatsch, Peter, Grabow, Desiree, Kaiser, Melanie, Spix, Claudia, Kremer, Leontien C., Calaminus, Gabriele, Baust, Katja, Kuehni, Claudia E., Weiss, Annette, Strebel, Sven, Kuonen, Rahel, Elsner, Susanne, Haupt, Riccardo, Garré, Maria Luisa, Gruhn, Bernd, Kepak, Tomas, Kepakova, Katerina, Winther, Jeanette Falck, Kenborg, Line, Rechnitzer, Catherine, Hasle, Henrik, Kruseova, Jarmila, Luks, Ales, Lackner, Herwig, Bielack, Stefan, Beck, Jörn Dirk, Jürgens, Heribert, van den Heuvel-Eibrink, Marry M., Zolk, Oliver, Eich, Hans Theodor, and am Zehnhoff-Dinnesen, Antoinette

Abstract

The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head-and-neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time-to-onset analysis. Eighty-eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow-up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P <.01). A time-to-onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P <.01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors.

Published
2024

9. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium

Author

Clemens, Eva, van den Heuvel-Eibrink, Marry M, Mulder, Renée L, Kremer, Leontien C M, Hudson, Melissa M, Skinner, Roderick, Constine, Louis S, Bass, Johnnie K, Kuehni, Claudia E, Langer, Thorsten, van Dalen, Elvira C, Bardi, Edith, Bonne, Nicolas-Xavier, Brock, Penelope R, Brooks, Beth, Carleton, Bruce, Caron, Eric, Chang, Kay W, Johnston, Karen, Knight, Kristin, Nathan, Paul C, Orgel, Etan, Prasad, Pinki K, Rottenberg, Jan, Scheinemann, Katrin, de Vries, Andrica C H, Walwyn, Thomas, Weiss, Annette, am Zehnhoff-Dinnesen, Antoinette, Cohn, Richard J, and Landier, Wendy

Published
2019
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10. PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents

Author

Kaatsch, P., Grabow, D., Byrne, J., Campbell, H., Clissmann, C., O'Brien, K., Kremer, L.C.M., Langer, T., van Dulmen-den Broeder, E., van den Berg, Dr. MH., van den Heuvel-Eibrink, M.M., Borgmann-Staudt, A., am Zehnhoff-Dinnesen, A., Kuehni, C.E., Haupt, R., Kepak, T., Berger, C., Winther, J.F., Kruseova, J., Calaminus, G., Baust, K., Dirksen, U., van Leeuwen, F., Schilling, R., Strauss, G., Ranft, A., Garré, M.-L., Fosså, S., Leiper, A., Lackner, H., Panasiuk, A., Krawczuk-Rybak, Dr. M., Kunstreich, M., Cario, H., Zolk, O., Bielack, S., Stefanowicz, J., Grandage, V., Modan, D., Paul, Norbert W., Knudsen, Lisbeth E., Byrne, Julianne, Grabow, Desiree, Campbell, Helen, O'Brien, Kylie, Bielack, Stefan, am Zehnhoff-Dinnesen, Antoinette, Calaminus, Gabriele, Kremer, Leontien, Langer, Thorsten, van den Heuvel-Eibrink, Marry M., van Dulmen-den Broeder, Eline, Baust, Katja, Bautz, Andrea, Beck, Jörn D., Berger, Claire, Binder, Harald, Borgmann-Staudt, Anja, Broer, Linda, Cario, Holger, Casagranda, Leonie, Clemens, Eva, Deuster, Dirk, de Vries, Andrica, Dirksen, Uta, Winther, Jeanette Falck, Fosså, Sophie, Font-Gonzalez, Anna, Grandage, Victoria, Haupt, Riccardo, Hecker-Nolting, Stefanie, Hjorth, Lars, Kaiser, Melanie, Kenborg, Line, Kepak, Tomas, Kepáková, Kateřina, Krawczuk-Rybak, Maryna, Kruseova, Jarmila, Kuehni, Claudia E., Kunstreich, Marina, Kuonen, Rahel, Lackner, Herwig, Leiper, Alison, Loeffen, Erik A.H., Luks, Ales, Modan-Moses, Dalit, Mulder, Renee, Parfitt, Ross, Ranft, Andreas, Ruud, Ellen, Schilling, Ralph, Spix, Claudia, Stefanowicz, Joanna, Strauβ, Gabriele, Uitterlinden, Andre G., van den Berg, Marleen, van der Kooi, Anne-Lotte, van Dijk, Marloes, van Leeuwen, Flora, Zolk, Oliver, Zöller, Daniela, and Kaatsch, Peter

Published
2018
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12. The impact of the temporal sequence of cranial radiotherapy and platin‐based chemotherapy on hearing impairment in pediatric and adolescent CNS and head‐and‐neck cancer patients: A report from the PanCareLIFE consortium.

Author

Scobioala, Sergiu, Parfitt, Ross, Matulat, Peter, Byrne, Julianne, Langer, Thorsten, Troschel, Fabian M., Hesping, Amélie E., Clemens, Eva, Kaatsch, Peter, Grabow, Desiree, Kaiser, Melanie, Spix, Claudia, Kremer, Leontien C., Calaminus, Gabriele, Baust, Katja, Kuehni, Claudia E., Weiss, Annette, Strebel, Sven, Kuonen, Rahel, and Elsner, Susanne

Subjects
HEARING disorders, CENTRAL nervous system tumors, CANCER patients, SENSORINEURAL hearing loss, TEENAGERS, CENTRAL nervous system
Abstract

The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin‐based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head‐and‐neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time‐to‐onset analysis. Eighty‐eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow‐up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P <.01). A time‐to‐onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P <.01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol

Author

van der Kooi, Anne-Lotte L. F., Clemens, Eva, Broer, Linda, Zolk, Oliver, Byrne, Julianne, Campbell, Helen, van den Berg, Marleen, Berger, Claire, Calaminus, Gabriele, Dirksen, Uta, Winther, Jeanette Falck, Fosså, Sophie D, Grabow, Desiree, Haupt, Riccardo, Kaiser, Melanie, Kepak, Tomas, Kremer, Leontien, Kruseova, Jarmila, Modan-Moses, Dalit, Ranft, Andreas, Spix, Claudia, Kaatsch, Peter, Laven, Joop S. E., van Dulmen-den Broeder, Eline, Uitterlinden, André G., van den Heuvel-Eibrink, Marry M., and on behalf of the PanCareLIFE Consortium

Published
2018
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14. Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study

Author

Clemens, Eva, Broer, Linda, Langer, Thorsten, Uitterlinden, André G., de Vries, Andrica C. H., van Grotel, Martine, Pluijm, Saskia F. M., Binder, Harald, Byrne, Julianne, Broeder, Eline van Dulmen-den, Crocco, Marco, Kaiser, Melanie, Kenborg, Line, Winther, Jeanette F., Rechnitzer, Catherine, Hasle, Henrik, van der Kooi, Anne-Lotte F., Kremer, Leontien C., van der Pal, Heleen, Parfitt, Ross, Deuster, Dirk, Matulat, Peter, Spix, Claudia, Tillmanns, Amelie, Tissing, Wim J. E., Maier, Lara, am Zehnhoff-Dinnesen, Antoinette, Zolk, Oliver, Kaatsch, P., Grabow, D., Campbell, H., O’Brien, K., Kremer, L.C.M., van Dulmen-den Broeder, E., van den Berg, M.H., van den Heuvel-Eibrink, M.M., Borgmann-Staudt, A., Kuehni, C.E., Haupt, R., Kepak, T., Berger, C., Winther, J.F., Kruseova, J., Calaminus, G., Baust, K., Dirksen, U., Kuehni, Claudia E., van den Heuvel-Eibrink, Marry M., Guided Treatment in Optimal Selected Cancer Patients (GUTS), Pediatric surgery, CCA - Cancer biology and immunology, Amsterdam Reproduction & Development (AR&D), Internal Medicine, Pediatrics, and Obstetrics & Gynecology

Subjects
Oncology, Male, Candidate gene, Internationality, Medizin, CHILDREN, VARIANTS, Neoplasms, TPMT, 610 Medicine & health, Child, SURVIVORS, Cumulative dose, Child, Preschool, Molecular Medicine, Sensorineural hearing loss, Female, 360 Social problems & social services, medicine.drug, medicine.medical_specialty, INDUCED HEARING-LOSS, Side effect, Adolescent, Single-nucleotide polymorphism, Antineoplastic Agents, PLATINUM CHEMOTHERAPY, ACYP2, Young Adult, Ototoxicity, Internal medicine, Genetics, medicine, Humans, Hearing Loss, Genetic Association Studies, Retrospective Studies, Pharmacology, Cisplatin, CHILDHOOD-CANCER, business.industry, Infant, Newborn, Genetic Variation, Infant, medicine.disease, COMT, REPLICATION, business
Abstract

Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8–21.5; P = 5.6 × 10−7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3–4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04–14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07–2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.

Published
2020
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15. The cumulative incidence of cisplatin‐induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments

Author

Meijer, Annelot J. M., primary, Li, Kathy H., additional, Brooks, Beth, additional, Clemens, Eva, additional, Ross, Colin J., additional, Rassekh, Sharad R., additional, Hoetink, Alex E., additional, Grotel, Martine, additional, Heuvel‐Eibrink, Marry M., additional, and Carleton, Bruce C., additional

Published
2021
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16. Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function

Author

Van Der Kooi, Anne Lotte L.F., Van Dijk, Marloes, Broer, Linda, Van Den Berg, Marleen H., Laven, Joop S.E., Van Leeuwen, Flora E., Lambalk, Cornelis B., Overbeek, Annelies, Loonen, Jacqueline J., Van Der Pal, Helena J., Tissing, Wim J., Versluys, Birgitta, Bresters, Dorine, Beerendonk, Catharina C.M., Ronckers, Cécile R., Van Der Heiden-Van Der Loo, Margriet, Kaspers, Gertjan L., De Vries, Andrica C.H., Robison, Leslie L., Hudson, Melissa M., Chemaitilly, Wassim, Byrne, Julianne, Berger, Claire, Clemens, Eva, Dirksen, Uta, Falck Winther, Jeanette, Fosså, Sophie D., Grabow, Desiree, Haupt, Riccardo, Kaiser, Melanie, Kepak, Tomas, Kruseova, Jarmila, Modan-Moses, Dalit, Pluijm, Saskia M.F., Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Krijthe, Jesse H., Kremer, Leontien C., Yasui, Yutaka, Brooke, Russell J., Uitterlinden, André G., Van Den Heuvel-Eibrink, Marry M., Van Dulmen-Den Broeder, Eline, Van Der Kooi, Anne Lotte L.F., Van Dijk, Marloes, Broer, Linda, Van Den Berg, Marleen H., Laven, Joop S.E., Van Leeuwen, Flora E., Lambalk, Cornelis B., Overbeek, Annelies, Loonen, Jacqueline J., Van Der Pal, Helena J., Tissing, Wim J., Versluys, Birgitta, Bresters, Dorine, Beerendonk, Catharina C.M., Ronckers, Cécile R., Van Der Heiden-Van Der Loo, Margriet, Kaspers, Gertjan L., De Vries, Andrica C.H., Robison, Leslie L., Hudson, Melissa M., Chemaitilly, Wassim, Byrne, Julianne, Berger, Claire, Clemens, Eva, Dirksen, Uta, Falck Winther, Jeanette, Fosså, Sophie D., Grabow, Desiree, Haupt, Riccardo, Kaiser, Melanie, Kepak, Tomas, Kruseova, Jarmila, Modan-Moses, Dalit, Pluijm, Saskia M.F., Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Krijthe, Jesse H., Kremer, Leontien C., Yasui, Yutaka, Brooke, Russell J., Uitterlinden, André G., Van Den Heuvel-Eibrink, Marry M., and Van Dulmen-Den Broeder, Eline

Abstract

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs116683

Published
2021

17. A comparison of genotyping arrays

Author

Verlouw, Joost A.M., Clemens, Eva, de Vries, Jard H., Zolk, Oliver, Verkerk, Annemieke J.M.H., am Zehnhoff-Dinnesen, Antoinette, Medina-Gomez, Carolina, Lanvers-Kaminsky, Claudia, Rivadeneira, Fernando, Langer, Thorsten, van Meurs, Joyce B.J., van den Heuvel-Eibrink, Marry M., Uitterlinden, André G., Broer, Linda, Verlouw, Joost A.M., Clemens, Eva, de Vries, Jard H., Zolk, Oliver, Verkerk, Annemieke J.M.H., am Zehnhoff-Dinnesen, Antoinette, Medina-Gomez, Carolina, Lanvers-Kaminsky, Claudia, Rivadeneira, Fernando, Langer, Thorsten, van Meurs, Joyce B.J., van den Heuvel-Eibrink, Marry M., Uitterlinden, André G., and Broer, Linda

Abstract

Array technology to genotype single-nucleotide variants (SNVs) is widely used in genome-wide association studies (GWAS), clinical diagnostics, and linkage studies. Arrays have undergone a tremendous growth in both number and content over recent years making a comprehensive comparison all the more important. We have compared 28 genotyping arrays on their overall content, genome-wide coverage, imputation quality, presence of known GWAS loci, mtDNA variants and clinically relevant genes (i.e., American College of Medical Genetics (ACMG) actionable genes, pharmacogenetic genes, human leukocyte antigen (HLA) genes and SNV density). Our comparison shows that genome-wide coverage is highly correlated with the number of SNVs on the array but does not correlate with imputation quality, which is the main determinant of GWAS usability. Average imputation quality for all tested arrays was similar for European and African populations, indicating that this is not a good criterion for choosing a genotyping array. Rather, the additional content on the array, such as pharmacogenetics or HLA variants, should be the deciding factor. As the research question of a study will in large part determine which class of genes are of interest, there is not just one perfect array for all different research questions. This study can thus help as a guideline to determine which array best suits a study’s requirements.

Published
2021

18. Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study

Author

SCT patientenzorg, MS VPG/Gynaecologie, Child Health, Cancer, van der Perk, M E Madeleine, Broer, Linda, Yasui, Yutaka, Robison, Leslie L, Hudson, Melissa M, Laven, Joop S E, van der Pal, Helena J, Tissing, Wim J E, Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J L, de Vries, Andrica C H, Lambalk, Cornelis B, Overbeek, Annelies, Loonen, Jacqueline J, Beerendonk, Catharina C M, Byrne, Julianne, Berger, Claire, Clemens, Eva, Dirksen, Uta, Falck Winther, Jeanette, Fosså, Sophie D, Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Krijthe, Jesse H, Kremer, Leontien C M, Brooke, Russell J, Baedke, Jessica L, van Schaik, Ron H N, van den Anker, John N, Uitterlinden, André G, Bos, Annelies M E, van Leeuwen, Flora E, van Dulmen-den Broeder, Eline, van der Kooi, Anne-Lotte L F, van den Heuvel-Eibrink, Marry M, On Behalf Of The PanCareLIFE Consortium, SCT patientenzorg, MS VPG/Gynaecologie, Child Health, Cancer, van der Perk, M E Madeleine, Broer, Linda, Yasui, Yutaka, Robison, Leslie L, Hudson, Melissa M, Laven, Joop S E, van der Pal, Helena J, Tissing, Wim J E, Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J L, de Vries, Andrica C H, Lambalk, Cornelis B, Overbeek, Annelies, Loonen, Jacqueline J, Beerendonk, Catharina C M, Byrne, Julianne, Berger, Claire, Clemens, Eva, Dirksen, Uta, Falck Winther, Jeanette, Fosså, Sophie D, Grabow, Desiree, Muraca, Monica, Kaiser, Melanie, Kepák, Tomáš, Kruseova, Jarmila, Modan-Moses, Dalit, Spix, Claudia, Zolk, Oliver, Kaatsch, Peter, Krijthe, Jesse H, Kremer, Leontien C M, Brooke, Russell J, Baedke, Jessica L, van Schaik, Ron H N, van den Anker, John N, Uitterlinden, André G, Bos, Annelies M E, van Leeuwen, Flora E, van Dulmen-den Broeder, Eline, van der Kooi, Anne-Lotte L F, van den Heuvel-Eibrink, Marry M, and On Behalf Of The PanCareLIFE Consortium

Published
2021

19. Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function

Author

van der Kooi, Anne-Lotte L F, primary, van Dijk, Marloes, additional, Broer, Linda, additional, van den Berg, Marleen H, additional, Laven, Joop S E, additional, van Leeuwen, Flora E, additional, Lambalk, Cornelis B, additional, Overbeek, Annelies, additional, Loonen, Jacqueline J, additional, van der Pal, Helena J, additional, Tissing, Wim J, additional, Versluys, Birgitta, additional, Bresters, Dorine, additional, Beerendonk, Catharina C M, additional, Ronckers, Cécile R, additional, van der Heiden-van der Loo, Margriet, additional, Kaspers, Gertjan L, additional, de Vries, Andrica C H, additional, Robison, Leslie L, additional, Hudson, Melissa M, additional, Chemaitilly, Wassim, additional, Byrne, Julianne, additional, Berger, Claire, additional, Clemens, Eva, additional, Dirksen, Uta, additional, Falck Winther, Jeanette, additional, Fosså, Sophie D, additional, Grabow, Desiree, additional, Haupt, Riccardo, additional, Kaiser, Melanie, additional, Kepak, Tomas, additional, Kruseova, Jarmila, additional, Modan-Moses, Dalit, additional, Pluijm, Saskia M F, additional, Spix, Claudia, additional, Zolk, Oliver, additional, Kaatsch, Peter, additional, Krijthe, Jesse H, additional, Kremer, Leontien C, additional, Yasui, Yutaka, additional, Brooke, Russell J, additional, Uitterlinden, André G, additional, van den Heuvel-Eibrink, Marry M, additional, and van Dulmen-den Broeder, Eline, additional

Published
2021
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20. Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset

Author

Langer, Thorsten, primary, Clemens, Eva, additional, Broer, Linda, additional, Maier, Lara, additional, Uitterlinden, André G., additional, de Vries, Andrica C.H., additional, van Grotel, Martine, additional, Pluijm, Saskia F.M., additional, Binder, Harald, additional, Mayer, Benjamin, additional, von dem Knesebeck, Annika, additional, Byrne, Julianne, additional, van Dulmen-den Broeder, Eline, additional, Crocco, Marco, additional, Grabow, Desiree, additional, Kaatsch, Peter, additional, Kaiser, Melanie, additional, Spix, Claudia, additional, Kenborg, Line, additional, Winther, Jeanette F., additional, Rechnitzer, Catherine, additional, Hasle, Henrik, additional, Kepak, Tomas, additional, van der Kooi, Anne-Lotte F., additional, Kremer, Leontien C., additional, Kruseova, Jarmila, additional, Bielack, Stefan, additional, Sorg, Benjamin, additional, Hecker-Nolting, Stefanie, additional, Kuehni, Claudia E., additional, Ansari, Marc, additional, Kompis, Martin, additional, van der Pal, Heleen J., additional, Parfitt, Ross, additional, Deuster, Dirk, additional, Matulat, Peter, additional, Tillmanns, Amelie, additional, Tissing, Wim J.E., additional, Beck, Jörn D., additional, Elsner, Susanne, additional, am Zehnhoff-Dinnesen, Antoinette, additional, van den Heuvel-Eibrink, Marry M., additional, and Zolk, Oliver, additional

Published
2020
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21. Possible Modification of BRSK1 on the Risk of Alkylating Chemotherapy-Related Reduced Ovarian Function

Author

van der Koi, A.-L., van Dijk, Melissa R., Broer, Linda, van den Berg, M., Laven, Joop Stephanus Elisabeth, van Leeuwen, Flora E., Lambalk, C. B. Nils, Overbeek, Annelies, Loonen, Jacqueline J., van der Pal, Helena J. H., Tissing, Wim J. E., Versluys, Birgitta A., Bresters, Dorine, Beerendonk, Catharina C. M., Ronckers, Cećile M., van der Heiden-van der Loo, Margriet, Kaspers, Gertjan Jan L., de Vries, Antoine A. F., Robison, LeslieL L., Hudson, Melissa Maria, Chemaitilly, Wassim, Byrne, Julianne M., Berger, Claire, Clemens, Eva, Dirksen, Uta, and Winther, Jeanette Falck

Subjects
Medizin
Abstract

Weitere Verfasser aus Einrichtungen außerhalb der Universität Duisburg-Essen sind nicht aufgeführt.

Published
2020

22. Clinical and genetic determinants of ototoxicity after childhood cancer

Author

Clemens, Eva, Eibrink, Marry, van Grotel, Martine, de Vries, A.C.H., and University Utrecht

Subjects
carboplatin, cisplatin, grading, platinum, guidelines, Ototoxicity, side-effect, hearing loss
Abstract

Approximately 550–600 children are diagnosed with cancer every year in the Netherlands. Improvements in treatment protocols brought a large increase in survival for many childhood cancers with a current overall long-term survival of ~80%. With the expansion of the childhood cancer survivor population, side-effects of treatment have become more prevalent and have drawn our attention. One of these side-effects is hearing impairment, induced by platinum treatment. The primary aim of this thesis was to investigate determinants of ototoxicity which occur during and after platinum treatment for childhood cancer. To compare five commonly used ototoxicity grading systems, we evaluated the concordance among the Brock, Chang, International Society of Pediatric Oncology (SIOP) Boston, U.S. National Cancer Institute Common Technology Criteria for Adverse Events (CTCAE) version 4.03, and Muenster ototoxicity grading scales using Kappa values. The results showed that the concordance among Muenster and Chang criteria was lowest (ĸ:0.636) and was highest among Chang and Brock criteria (ĸ:0.975). We then evaluated the time to detection of hearing loss. In general, Muenster detected hearing loss the earliest in time, followed by Chang, SIOP and Brock. We subsequently analyzed the frequency and determinants of ototoxicity in a cross-sectional multicenter study. Ototoxicity seems to be influenced by the type of platinum and dose of cisplatin. For patients treated with a cumulative cisplatin dose of 300 mg/m2 or more, a 5-fold higher risk of ototoxicity was observed, compared with patients treated with a lower cumulative cisplatin dose. Furthermore, young age at diagnosis, concomitant carboplatin use and furosemide co-treatment increased the risk for hearing impairment in childhood cancer patients treated with platinum agents, but not treated with cranial irradiation. While many factors influence hearing impairment during and after platinum treatment, genetic factors have been suggested to play a role in ototoxicity as well. Evidence from previous studies looking for associations between genetic variation and ototoxicity was largely insufficient or inconclusive, due to failure of independent replication or the small sample size, limiting statistical power. Our candidate gene approach could not replicate the evidence for the single nucleotide polymorphisms in ACYP2, LRP2, NFE2L2, OTOS, TPMT, SOD2, SLC22A2, GSTP1, ABCC3 and SLC16A5 genes being associated with ototoxicity. However, meta-analysis of all available literature showed that rs1872328 in ACYP2 could possibly be related to platinum ototoxicity in childhood cancer patients and survivors. As platinum-treated or cranial irradiated childhood cancer survivors have an increased risk of developing ototoxicity, clinical practice guidelines are necessary to promote early detection. Clinical practice guidelines for long-term follow-up of childhood cancer survivors have been developed by groups in North America and Europe, but recommendations vary among existing guidelines. This results in duplication of work and uncertainty for both survivor and health care providers which guideline to follow. The International Late Effects of Childhood Cancer Guideline Harmonization Group has been initiated to harmonize clinical practice guidelines for childhood cancer survivors. We described the overall methods of our worldwide collaborative effort to harmonize the recommendations for surveillance of ototoxicity after treatment for childhood and young adult cancer.

Published
2019

23. Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset

Author

Langer, T, Clemens, Eva, Broer, Linda, Maier, L, Uitterlinden, André, Vries, ACH, van Grotel, Martine, Pluijm, Saskia F.M., Binder, H, Mayer, Benjamin, von dem Knesebeck, A, Byrne, J, van Dulmen-den Broeder, E, Crocco, M, Grabow, D, Kaatsch, P, Kaiser, M, Spix, C, Kenborg, L, Winther, JF, Rechnitzer, C, Hasle, H, Kepak, T, Kooi, Anne-Lotte, Kremer, LC, Kruseova, J, Bielack, S, Sorg, B, Hecker-Nolting, S, Kuehni, CE, Ansari, M, Kompis, M, van der Pal, HJ, Parfitt, R, Deuster, D, Matulat, P, Tillmanns, A, Tissing, WJ, Beck, JD, Elsner, S, am Zehnhoff-Dinnesen, A, Eibrink, Marry, Zolk, O, Langer, T, Clemens, Eva, Broer, Linda, Maier, L, Uitterlinden, André, Vries, ACH, van Grotel, Martine, Pluijm, Saskia F.M., Binder, H, Mayer, Benjamin, von dem Knesebeck, A, Byrne, J, van Dulmen-den Broeder, E, Crocco, M, Grabow, D, Kaatsch, P, Kaiser, M, Spix, C, Kenborg, L, Winther, JF, Rechnitzer, C, Hasle, H, Kepak, T, Kooi, Anne-Lotte, Kremer, LC, Kruseova, J, Bielack, S, Sorg, B, Hecker-Nolting, S, Kuehni, CE, Ansari, M, Kompis, M, van der Pal, HJ, Parfitt, R, Deuster, D, Matulat, P, Tillmanns, A, Tissing, WJ, Beck, JD, Elsner, S, am Zehnhoff-Dinnesen, A, Eibrink, Marry, and Zolk, O

Published
2020

24. Risk factors associated with tinnitus in 2948 Dutch survivors of childhood cancer: a Dutch LATER questionnaire study

Author

MS Radiotherapie, Cancer, PMC Medisch specialisten, Child Health, Zorgeenheid KNO Medisch, Brain, Audiologen, Meijer, Annelot J M, Fiocco, Marta F, Janssens, Geert O, Clemens, Eva, Tissing, Wim J E, Loonen, Jacqueline J, van Dulmen-den Broeder, Eline, de Vries, Andrica C H, Bresters, Dorine, Versluys, Birgitta, Ronckers, Cécile M, Kremer, Leontien C M, van der Pal, Helena J, Neggers, Sebastian J C M M, van der Heiden-van der Loo, Margriet, Stokroos, Robert J, Hoetink, Alex E, van Grotel, Martine, van den Heuvel-Eibrink, Marry M, MS Radiotherapie, Cancer, PMC Medisch specialisten, Child Health, Zorgeenheid KNO Medisch, Brain, Audiologen, Meijer, Annelot J M, Fiocco, Marta F, Janssens, Geert O, Clemens, Eva, Tissing, Wim J E, Loonen, Jacqueline J, van Dulmen-den Broeder, Eline, de Vries, Andrica C H, Bresters, Dorine, Versluys, Birgitta, Ronckers, Cécile M, Kremer, Leontien C M, van der Pal, Helena J, Neggers, Sebastian J C M M, van der Heiden-van der Loo, Margriet, Stokroos, Robert J, Hoetink, Alex E, van Grotel, Martine, and van den Heuvel-Eibrink, Marry M

Published
2020

25. The cumulative incidence of cisplatin‐induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments.

Author

Meijer, Annelot J. M., Li, Kathy H., Brooks, Beth, Clemens, Eva, Ross, Colin J., Rassekh, Sharad R., Hoetink, Alex E., van Grotel, Martine, van den Heuvel‐Eibrink, Marry M., and Carleton, Bruce C.

Subjects
HEARING disorders, CHILD death, CHILDHOOD cancer, PEDIATRIC oncology, CISPLATIN, OTOTOXICITY, CONDUCTIVE hearing loss
Abstract

Background: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin‐induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. Methods: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan‐Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. Results: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%‐84%), with a rapid increase observed to 27% (95% CI, 21%‐35%) at 3 months and to 61% (95% CI, 53%‐69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%‐62%; P <.001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01‐1.41) vincristine (HR, 2.87; 95% CI, 1.89‐4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17‐2.95) further influenced CIHL development over time. Conclusions: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co‐)medication. These results highlight the need for audiological monitoring at each cisplatin cycle. In young children, the cumulative incidence of cisplatin‐induced hearing loss is higher compared with that in older children and develops early during therapy. The course of cisplatin‐induced hearing loss development over time is further influenced by the total cumulative dose of cisplatin, vincristine treatment, and total duration of concomitantly administered antibiotics. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Usefulness of Current Candidate Genetic Markers to Identify Childhood Cancer Patients at Risk for Platinum-Induced Ototoxicity: Results of the European PanCareLIFE Cohort Study

Author

Langer, Thorsten, primary, Clemens, Eva, additional, Broer, Linda, additional, Maier, Lara, additional, Uitterlinden, Andre G., additional, de Vries, Andrica C. H., additional, van Grotel, Martine, additional, Pluijm, Saskia F.M., additional, Binder, Harald, additional, Mayer, Benjamin, additional, von dem Knesebeck, Annika, additional, Byrne, Julianne, additional, van Dulmen-den Broeder, Eline, additional, Crocco, Marco, additional, Grabow, Desiree, additional, Kaatsch, Peter, additional, Kaiser, Melanie, additional, Spix, Claudia, additional, Kenborg, Line, additional, Winther, Jeanette Falck, additional, Rechnitzer, Catherine, additional, Hasle, Henrik, additional, Kepak, Tomas, additional, van der Kooi, Anne-Lotte F., additional, Kremer, Leontien C., additional, Kruseova, Jarmila, additional, Bielack, Stefan, additional, Sorg, Benjamin, additional, Hecker-Nolting, Stefanie, additional, Kuehni, Claudia E., additional, Ansari, Marc, additional, Kompis, Martin, additional, van der Pal, Heleen, additional, Parfitt, Ross, additional, Deuster, Dirk, additional, Matulat, Peter, additional, Tillmanns, Amelie, additional, Tissing, Wim J. E., additional, Beck, Jörn D., additional, Elsner, Susanne, additional, am Zehnhoff-Dinnesen, Antoinette, additional, van den Heuvel-Eibrink, Marry M., additional, Zolk, Oliver, additional, and Group, PanCareLIFE Consortium, additional

Published
2020
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27. Risk factors associated with tinnitus in 2948 Dutch survivors of childhood cancer: a Dutch LATER questionnaire study

Author

Meijer, Annelot J M, primary, Fiocco, Marta F, additional, Janssens, Geert O, additional, Clemens, Eva, additional, Tissing, Wim J E, additional, Loonen, Jacqueline J, additional, van Dulmen-den Broeder, Eline, additional, de Vries, Andrica C H, additional, Bresters, Dorine, additional, Versluys, Birgitta, additional, Ronckers, Cécile M, additional, Kremer, Leontien C M, additional, van der Pal, Helena J, additional, Neggers, Sebastian J C M M, additional, van der Heiden-van der Loo, Margriet, additional, Stokroos, Robert J, additional, Hoetink, Alex E, additional, van Grotel, Martine, additional, and van den Heuvel-Eibrink, Marry M, additional

Published
2020
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28. Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study

Author

Clemens, Eva, primary, Meijer, Annelot JM, additional, Broer, Linda, additional, Langer, Thorsten, additional, van der Kooi, Anne-Lotte LF, additional, Uitterlinden, André G, additional, de Vries, Andrica, additional, Kuehni, Claudia E, additional, Garrè, Maria L, additional, Kepak, Tomas, additional, Kruseova, Jarmila, additional, Winther, Jeanette F, additional, Kremer, Leontien C, additional, van Dulmen-den Broeder, Eline, additional, Tissing, Wim JE, additional, Rechnitzer, Catherine, additional, Kenborg, Line, additional, Hasle, Henrik, additional, Grabow, Desiree, additional, Parfitt, Ross, additional, Binder, Harald, additional, Carleton, Bruce C, additional, Byrne, Julianne, additional, Kaatsch, Peter, additional, am Zehnhoff-Dinnesen, Antoinette, additional, Zolk, Oliver, additional, and van den Heuvel-Eibrink, Marry M, additional

Published
2019
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31. Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study

Author

Clemens, Eva, Meijer, AJM, Broer, Linda, Langer, T, van der Kooi, Anne-Lotte, Uitterlinden, André, de Vries, A.C.H., Kuehni, CE, Garre, ML, Kepak, T, Kruseova, J, Winther, JF, Kremer, LC, van Dulmen-den Broeder, E, Tissing, WJ, Rechnitzer, C, Kenborg, L, Hasle, H, Grabow, D, Parfitt, R, Binder, H, Carleton, BC, Byrne, J, Kaatsch, P, Zehnhoff-Dinnesen, AA, Zolk, O, Van den Heuvel - Eibrink, Marry, Clemens, Eva, Meijer, AJM, Broer, Linda, Langer, T, van der Kooi, Anne-Lotte, Uitterlinden, André, de Vries, A.C.H., Kuehni, CE, Garre, ML, Kepak, T, Kruseova, J, Winther, JF, Kremer, LC, van Dulmen-den Broeder, E, Tissing, WJ, Rechnitzer, C, Kenborg, L, Hasle, H, Grabow, D, Parfitt, R, Binder, H, Carleton, BC, Byrne, J, Kaatsch, P, Zehnhoff-Dinnesen, AA, Zolk, O, and Van den Heuvel - Eibrink, Marry

Published
2019

33. PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents

Author

Byrne, Julianne, primary, Grabow, Desiree, additional, Campbell, Helen, additional, O'Brien, Kylie, additional, Bielack, Stefan, additional, am Zehnhoff-Dinnesen, Antoinette, additional, Calaminus, Gabriele, additional, Kremer, Leontien, additional, Langer, Thorsten, additional, van den Heuvel-Eibrink, Marry M., additional, van Dulmen-den Broeder, Eline, additional, Baust, Katja, additional, Bautz, Andrea, additional, Beck, Jörn D., additional, Berger, Claire, additional, Binder, Harald, additional, Borgmann-Staudt, Anja, additional, Broer, Linda, additional, Cario, Holger, additional, Casagranda, Leonie, additional, Clemens, Eva, additional, Deuster, Dirk, additional, de Vries, Andrica, additional, Dirksen, Uta, additional, Winther, Jeanette Falck, additional, Fosså, Sophie, additional, Font-Gonzalez, Anna, additional, Grandage, Victoria, additional, Haupt, Riccardo, additional, Hecker-Nolting, Stefanie, additional, Hjorth, Lars, additional, Kaiser, Melanie, additional, Kenborg, Line, additional, Kepak, Tomas, additional, Kepáková, Kateřina, additional, Knudsen, Lisbeth E., additional, Krawczuk-Rybak, Maryna, additional, Kruseova, Jarmila, additional, Kuehni, Claudia E., additional, Kunstreich, Marina, additional, Kuonen, Rahel, additional, Lackner, Herwig, additional, Leiper, Alison, additional, Loeffen, Erik A.H., additional, Luks, Ales, additional, Modan-Moses, Dalit, additional, Mulder, Renee, additional, Parfitt, Ross, additional, Paul, Norbert W., additional, Ranft, Andreas, additional, Ruud, Ellen, additional, Schilling, Ralph, additional, Spix, Claudia, additional, Stefanowicz, Joanna, additional, Strauβ, Gabriele, additional, Uitterlinden, Andre G., additional, van den Berg, Marleen, additional, van der Kooi, Anne-Lotte, additional, van Dijk, Marloes, additional, van Leeuwen, Flora, additional, Zolk, Oliver, additional, Zöller, Daniela, additional, Kaatsch, Peter, additional, Kaatsch, P., additional, Grabow, D., additional, Byrne, J., additional, Campbell, H., additional, Clissmann, C., additional, O'Brien, K., additional, Kremer, L.C.M., additional, Langer, T., additional, van Dulmen-den Broeder, E., additional, van den Berg, Dr. MH., additional, van den Heuvel-Eibrink, M.M., additional, Borgmann-Staudt, A., additional, am Zehnhoff-Dinnesen, A., additional, Kuehni, C.E., additional, Haupt, R., additional, Kepak, T., additional, Berger, C., additional, Winther, J.F., additional, Kruseova, J., additional, Calaminus, G., additional, Baust, K., additional, Dirksen, U., additional, van Leeuwen, F., additional, Schilling, R., additional, Strauss, G., additional, Ranft, A., additional, Garré, M.-L., additional, Fosså, S., additional, Leiper, A., additional, Lackner, H., additional, Panasiuk, A., additional, Krawczuk-Rybak, Dr. M., additional, Kunstreich, M., additional, Cario, H., additional, Zolk, O., additional, Bielack, S., additional, Stefanowicz, J., additional, Grandage, V., additional, and Modan, D., additional

Published
2018
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34. Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study (Preprint)

Author

Clemens, Eva, primary, Meijer, Annelot JM, additional, Broer, Linda, additional, Langer, Thorsten, additional, van der Kooi, Anne-Lotte LF, additional, Uitterlinden, André G, additional, de Vries, Andrica, additional, Kuehni, Claudia E, additional, Garrè, Maria L, additional, Kepak, Tomas, additional, Kruseova, Jarmila, additional, Winther, Jeanette F, additional, Kremer, Leontien C, additional, van Dulmen-den Broeder, Eline, additional, Tissing, Wim JE, additional, Rechnitzer, Catherine, additional, Kenborg, Line, additional, Hasle, Henrik, additional, Grabow, Desiree, additional, Parfitt, Ross, additional, Binder, Harald, additional, Carleton, Bruce C, additional, Byrne, Julianne, additional, Kaatsch, Peter, additional, am Zehnhoff-Dinnesen, Antoinette, additional, Zolk, Oliver, additional, and van den Heuvel-Eibrink, Marry M, additional

Published
2018
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35. PanCareLIFE:The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents

Author

Byrne, Julianne, Grabow, Desiree, Campbell, Helen, O'Brien, Kylie, Bielack, Stefan, Zehnhoff-Dinnesen, Antoinette Am, Calaminus, Gabriele, Kremer, Leontien, Langer, Thorsten, van den Heuvel-Eibrink, Marry M., van Dulmen-den Broeder, Eline, Baust, Katja, Bautz, Andrea, Beck, Jörn D., Berger, Claire, Binder, Harald, Borgmann-Staudt, Anja, Broer, Linda, Cario, Holger, Casagranda, Leonie, Clemens, Eva, Deuster, Dirk, de Vries, Andrica, Dirksen, Uta, Winther, Jeanette Falck, Fossa, Sophie, Font-Gonzalez, Anna, Grandage, Victoria, Haupt, Riccardo, Hecker-Nolting, Stefanie, Hjorth, Lars, Kaiser, Melanie, Kenborg, Line, Kepak, Tomas, Kepakova, Katerina, Knudsen, Lisbeth E., Krawczuk-Rybak, Maryna, Kruseova, Jarmila, Kuehni, Claudia E., Kunstreich, Marina, Kuonen, Rahel, Lackner, Herwig, Leiper, Alison, Loeffen, Erik A. H., Luks, Ales, Modan-Moses, Dalit, Mulder, Renee, Parfitt, Ross, Paul, Norbert W., Ranft, Andreas, Ruud, Ellen, Schilling, Ralph, Spix, Claudia, Stefanowicz, Joanna, Strauss, Gabriele, Uitterlinden, Andre G., van den Berg, Marleen, van der Kooi, Anne-Lotte, van Dijk, Marloes, van Leeuwen, Flora, Zolk, Oliver, Zoeller, Daniela, Kaatsch, Peter, Byrne, Julianne, Grabow, Desiree, Campbell, Helen, O'Brien, Kylie, Bielack, Stefan, Zehnhoff-Dinnesen, Antoinette Am, Calaminus, Gabriele, Kremer, Leontien, Langer, Thorsten, van den Heuvel-Eibrink, Marry M., van Dulmen-den Broeder, Eline, Baust, Katja, Bautz, Andrea, Beck, Jörn D., Berger, Claire, Binder, Harald, Borgmann-Staudt, Anja, Broer, Linda, Cario, Holger, Casagranda, Leonie, Clemens, Eva, Deuster, Dirk, de Vries, Andrica, Dirksen, Uta, Winther, Jeanette Falck, Fossa, Sophie, Font-Gonzalez, Anna, Grandage, Victoria, Haupt, Riccardo, Hecker-Nolting, Stefanie, Hjorth, Lars, Kaiser, Melanie, Kenborg, Line, Kepak, Tomas, Kepakova, Katerina, Knudsen, Lisbeth E., Krawczuk-Rybak, Maryna, Kruseova, Jarmila, Kuehni, Claudia E., Kunstreich, Marina, Kuonen, Rahel, Lackner, Herwig, Leiper, Alison, Loeffen, Erik A. H., Luks, Ales, Modan-Moses, Dalit, Mulder, Renee, Parfitt, Ross, Paul, Norbert W., Ranft, Andreas, Ruud, Ellen, Schilling, Ralph, Spix, Claudia, Stefanowicz, Joanna, Strauss, Gabriele, Uitterlinden, Andre G., van den Berg, Marleen, van der Kooi, Anne-Lotte, van Dijk, Marloes, van Leeuwen, Flora, Zolk, Oliver, Zoeller, Daniela, and Kaatsch, Peter

Published
2018

36. Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol

Author

van der Kooi, Anne-Lotte, Clemens, Eva, Broer, Linda, Zolk, O, Byrne, J, Campbell, H, Berg, M, Berger, C, Calaminus, G, Dirksen, U, Winther, JF, Fossa, SD, Grabow, D, Haupt, R, Kaiser, M, Kepak, T, Kremer, L, Kruseova, J, Modan-Moses, D, Ranft, A, Spix, C, Kaatsch, P, Laven, Joop, van Dulmen-den Broeder, E, Uitterlinden, André, Van den Heuvel - Eibrink, Marry, van der Kooi, Anne-Lotte, Clemens, Eva, Broer, Linda, Zolk, O, Byrne, J, Campbell, H, Berg, M, Berger, C, Calaminus, G, Dirksen, U, Winther, JF, Fossa, SD, Grabow, D, Haupt, R, Kaiser, M, Kepak, T, Kremer, L, Kruseova, J, Modan-Moses, D, Ranft, A, Spix, C, Kaatsch, P, Laven, Joop, van Dulmen-den Broeder, E, Uitterlinden, André, and Van den Heuvel - Eibrink, Marry

Published
2018

37. The influence of genetic variation on late toxicities in childhood cancer survivors: A review

Author

Clemens, Eva, van der Kooi, Anne-Lotte, Broer, Linda, van Dulmen-den Broeder, E, Visscher, H, Kremer, L, Tissing, W, Loonen, J, Ronckers, CM, Pluijm, Saskia, Neggers, S.J.C.M.M., Zolk, O, Langer, T, Zehnhoff-Dinnese, AA, Wilson, CL, Hudson, MM, Carleton, B, Laven, Joop, Uitterlinden, André, Van den Heuvel - Eibrink, Marry, Clemens, Eva, van der Kooi, Anne-Lotte, Broer, Linda, van Dulmen-den Broeder, E, Visscher, H, Kremer, L, Tissing, W, Loonen, J, Ronckers, CM, Pluijm, Saskia, Neggers, S.J.C.M.M., Zolk, O, Langer, T, Zehnhoff-Dinnese, AA, Wilson, CL, Hudson, MM, Carleton, B, Laven, Joop, Uitterlinden, André, and Van den Heuvel - Eibrink, Marry

Published
2018

40. Socio-demographic impact of platinum-induced ototoxicity in long-term survivors of childhood cancer

Author

Clemens, Eva, van Doorn, Martijn, Neggers, S.J.C.M.M., de Vries, Andrica C.H., van den Heuvel-Eibrink, M. M., Clemens, Eva, van Doorn, Martijn, Neggers, S.J.C.M.M., de Vries, Andrica C.H., and van den Heuvel-Eibrink, M. M.

Abstract

Objective: Childhood cancer survivors (CCS) treated with platinum-based chemotherapy are at risk of treatment-induced ototoxicity. To date, there is limited knowledge on the effect of ototoxicity on socio-demographic factors, the burden to obtain insurances and psychological distress in CCS. Design: Of the 653 CCS with completed questionnaires, 54 survivors had been treated with platinum. Ototoxicity (Münster score ≥ 2b) data were retrieved from pure-tone audiometry. All survivors completed a questionnaire consisting of the Distress Thermometer (DT), measuring the severity of distress and was recoded to a 0 (no distress)-10 (extreme distress) scale. The Hospital Anxiety and Depression Scale (HADS) was used to study the psychological distress (a score ≥ 15 is indicative for clinically significant distress). Results: Median age at diagnosis was 6.2 years (range: 0.01-17.8) and median follow-up time from end of treatment to questionnaire was 15.6 years (range: 3.2-43.7). There were no differences in attempts to obtain insurances, highest education achievement and (un) employment between platinum-treated survivors and non-platinum treated survivors. Among the 54 platinum-treated CCS, median HADS score of hearing impaired survivors (n=22 (median score: 4.5, range: 0.0-29)) was not significantly different from survivors without ototoxicity (n=32 (median score 5.5, range: 0.0-11, p=0.337)). Similarly, DT scores were not significantly different between survivors with or without ototoxicity (p=0.441). Compared to the 599 non-platinum treated survivors, median HADS and DT scores of platinum-treated survivors were not significantly different. Conclusion: Based on this first, small study, we didn't find differences between CCS who suffer from platinum-related ototoxicity and survivors without hearing impairment, suggesting that CCS with ototoxicity do not necessarily encounter more socio-demographic challenges and psych

Published
2017

41. Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors

Author

Clemens, Eva, de Vries, Andrica C H, Am Zehnhoff-Dinnesen, Antoinette, Tissing, Wim J.E., Loonen, Jacqueline J, Pluijm, Saskia F.M., Van Dulmen-Den Broeder, Eline, Bresters, Dorine, Versluys, Birgitta, Kremer, Leontien C M, van der Pal, Helena J., Neggers, Sebastian J C M M, van Grotel, Martine, M van den Heuvel-Eibrink, Marry, Clemens, Eva, de Vries, Andrica C H, Am Zehnhoff-Dinnesen, Antoinette, Tissing, Wim J.E., Loonen, Jacqueline J, Pluijm, Saskia F.M., Van Dulmen-Den Broeder, Eline, Bresters, Dorine, Versluys, Birgitta, Kremer, Leontien C M, van der Pal, Helena J., Neggers, Sebastian J C M M, van Grotel, Martine, and M van den Heuvel-Eibrink, Marry

Published
2017

42. Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors

Author

PMC Research, Haematologie patientenzorg, Child Health, PMC Medisch specialisten, Clemens, Eva, de Vries, Andrica C H, Am Zehnhoff-Dinnesen, Antoinette, Tissing, Wim J.E., Loonen, Jacqueline J, Pluijm, Saskia F.M., Van Dulmen-Den Broeder, Eline, Bresters, Dorine, Versluys, Birgitta, Kremer, Leontien C M, van der Pal, Helena J., Neggers, Sebastian J C M M, van Grotel, Martine, M van den Heuvel-Eibrink, Marry, PMC Research, Haematologie patientenzorg, Child Health, PMC Medisch specialisten, Clemens, Eva, de Vries, Andrica C H, Am Zehnhoff-Dinnesen, Antoinette, Tissing, Wim J.E., Loonen, Jacqueline J, Pluijm, Saskia F.M., Van Dulmen-Den Broeder, Eline, Bresters, Dorine, Versluys, Birgitta, Kremer, Leontien C M, van der Pal, Helena J., Neggers, Sebastian J C M M, van Grotel, Martine, and M van den Heuvel-Eibrink, Marry

Published
2017

43. Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors

Author

Clemens, Eva, primary, de Vries, Andrica CH, additional, am Zehnhoff-Dinnesen, Antoinette, additional, Tissing, Wim JE, additional, Loonen, Jacqueline J, additional, Pluijm, Saskia FM, additional, van Dulmen-den Broeder, Eline, additional, Bresters, Dorine, additional, Versluys, Birgitta, additional, Kremer, Leontien CM, additional, van der Pal, Helena J, additional, Neggers, Sebastian JCCM, additional, van Grotel, Martine, additional, and M van den Heuvel-Eibrink, Marry, additional

Published
2017
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44. Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study

Author

PMC Research, Haematologie patientenzorg, Child Health, PMC Medisch specialisten, Zorg en O&O, Clemens, Eva, de Vries, Andrica C, Pluijm, Saskia F, Am Zehnhoff-Dinnesen, Antoinette, Tissing, Wim J, Loonen, Jacqueline J, van Dulmen-den Broeder, Eline, Bresters, Dorine, Versluys, Birgitta, Kremer, Leontien C, van der Pal, Heleen J, van Grotel, Martine, van den Heuvel-Eibrink, Marry M, DCOG-LATER, The Netherlands, PMC Research, Haematologie patientenzorg, Child Health, PMC Medisch specialisten, Zorg en O&O, Clemens, Eva, de Vries, Andrica C, Pluijm, Saskia F, Am Zehnhoff-Dinnesen, Antoinette, Tissing, Wim J, Loonen, Jacqueline J, van Dulmen-den Broeder, Eline, Bresters, Dorine, Versluys, Birgitta, Kremer, Leontien C, van der Pal, Heleen J, van Grotel, Martine, van den Heuvel-Eibrink, Marry M, and DCOG-LATER, The Netherlands

Published
2016

46. Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study.

Author

van der Perk, M. E. Madeleine, Broer, Linda, Yasui, Yutaka, Robison, Leslie L., Hudson, Melissa M., Laven, Joop S. E., van der Pal, Helena J., Tissing, Wim J. E., Versluys, Birgitta, Bresters, Dorine, Kaspers, Gertjan J. L., de Vries, Andrica C. H., Lambalk, Cornelis B., Overbeek, Annelies, Loonen, Jacqueline J., Beerendonk, Catharina C. M., Byrne, Julianne, Berger, Claire, Clemens, Eva, and Dirksen, Uta

Subjects
OVARIES, CYTOCHROME P-450, CONFIDENCE intervals, META-analysis, GONADAL diseases, CANCER chemotherapy, GENETIC polymorphisms, ANTINEOPLASTIC agents, GENETIC variation, REGRESSION analysis, TUMORS in children, CANCER patients, RISK assessment, SEX hormones, CYCLOPHOSPHAMIDE, DESCRIPTIVE statistics, DRUG side effects, LOGISTIC regression analysis, LONGITUDINAL method
Abstract

Simple Summary: Childhood cancer patients receiving treatment containing alkylating agents are at risk of infertility, yet inter-individual variability in treatment-related ovarian damage is observed. Alkylating agents are metabolized by cytochrome P450 (CYP450) enzymes and polymorphisms in these CYP450 enzymes may explain this variability in ovarian damage. This study on genetic variation in CYP450 enzymes of chemotherapy-induced gonadotoxicity, using anti-Müllerian hormone (AMH) levels as a proxy for ovarian reserve, in female childhood cancer survivors (CCSs) may identify patients at risk of infertility. This unique global collaboration of two large CCS studies shows the significant gonadotoxic effect of enzyme CYP3A4*3 and significant protective effect of CYP2B6*2 on gonadal function in CCSs receiving alkylating agents. Genetic variation in CYP3A4 and CYP2B6 have previously been associated with gonadotoxicity after cancer treatment. These findings could guide risk prediction models determining patients at risk of chemotherapy-induced gonadal impairment. Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1–30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6–37.4). Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): −0.706 (−1.11–−0.298), p-value = 7 × 10−4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126–0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study

Author

Clemens, Eva, Meijer, Annelot Jm, Broer, Linda, Langer, Thorsten, Van Der Kooi, Anne-Lotte Lf, Uitterlinden, André G, De Vries, Andrica, Kuehni, Claudia E, Garrè, Maria L, Kepak, Tomas, Kruseova, Jarmila, Winther, Jeanette F, Kremer, Leontien C, Van Dulmen-Den Broeder, Eline, Tissing, Wim Je, Rechnitzer, Catherine, Kenborg, Line, Hasle, Henrik, Grabow, Desiree, Parfitt, Ross, Binder, Harald, Carleton, Bruce C, Byrne, Julianne, Kaatsch, Peter, Am Zehnhoff-Dinnesen, Antoinette, Zolk, Oliver, and Van Den Heuvel-Eibrink, Marry M

Subjects
020 Library & information sciences, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

BACKGROUND Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication. OBJECTIVE We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity. METHODS As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening. RESULTS This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020. CONCLUSIONS Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/11868.

48. Platin treatment and hearing loss: initial audiological results from PanCareLIFE

Author

Parfitt, Ross, Tillmanns, Amelie, Matulat, Peter, Deuster, Dirk, Elsner, Susanne, Wolschon, Eva-Maria, Kuehni, Claudia E., Kuonen, Rahel, Weiss, Annette, Garré, Marie-Luisa, Kepak, Tomas, Kepakova, Katerina, Kruseova, Jarmila, Luks, Ales, Falck Winther, Jeanette, Kenborg, Line, Lackner, Herwig, Bielack, Stefan, van den Heuvel-Eibrink, Marry, Calaminus, Gabriele, Baust, Katja, Beck, Jörn, Kremer, Leontien, Clemens, Eva, Langer, Thorsten, Zolk, Oliver, and am Zehnhoff-Dinnesen, Antoinette

Subjects
610 Medical sciences, Medicine, 3. Good health
Abstract

Background Cisplatin and carboplatin are widely used in paediatric cancer treatment. Cisplatin especially can have long-term side effects, including sensorineural hearing loss. The aim of this study is to define the risk factors for platin-related ototoxicity. Materials and Methods As part [for full text, please go to the a.m. URL], 36. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP)

49. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium

Author

Clemens, Eva, Van Den Heuvel-Eibrink, Marry M, Mulder, Renée L, Kremer, Leontien C M, Hudson, Melissa M, Skinner, Roderick, Constine, Louis S, Bass, Johnnie K, Kuehni, Claudia E, Langer, Thorsten, Van Dalen, Elvira C, Bardi, Edith, Bonne, Nicolas-Xavier, Brock, Penelope R, Brooks, Beth, Carleton, Bruce, Caron, Eric, Chang, Kay W, Johnston, Karen, Knight, Kristin, Nathan, Paul C, Orgel, Etan, Prasad, Pinki K, Rottenberg, Jan, Scheinemann, Katrin, De Vries, Andrica C H, Walwyn, Thomas, Weiss, Annette, Am Zehnhoff-Dinnesen, Antoinette, Cohn, Richard J, and Landier, Wendy

Subjects
otorhinolaryngologic diseases, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.

50. Confirmation of genetic risk markers of platinum-induced ototoxicity

Author

Tillmanns, Amelie, Parfitt, Ross, Matulat, Peter, Abdel-Kahaar, Emaad, Maier, Lara, Zolk, Oliver, Elsner, Susanne, Wolschon, Eva-Maria, Kuehni, Claudia E., Kuonen, Rahel, Weiss, Annette, Garré, Marie-Luisa, Kepak, Tomas, Kepakova, Katerina, Kruseova, Jarmila, Luks, Ales, Falck Winther, Jeanette, Kenborg, Line, Lackner, Herwig, Bielack, Stefan, van den Heuvel-Eibrink, Marry, Calaminus, Gabriele, Baust, Katja, Beck, Jörn, Kremer, Leontien, Clemens, Eva, Langer, Thorsten, am Zehnhoff-Dinnesen, Antoinette, and PanCareLIFE Consortium

Subjects
610 Medical sciences, Medicine, 3. Good health
Abstract

Background Platinum compounds such as cisplatin or carboplatin are potent antineoplastic agents widely used for a variety of cancer types. Unfortunately, their use leads to dose-limiting side effects such as ototoxicity. Our study aimed at investigating the predictive value of 11 candidate genetic[for full text, please go to the a.m. URL], 36. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP)

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