Search

Your search keyword '"Zolk O"' showing total 235 results
Start Over Author "Zolk O"
235 results on '"Zolk O"'

3. PreVitaCOV - Prednisolon und Vitamin B1, B6 und B12 bei Post-COVID: Erfahrungen nach einem halben Jahr Rekrutierung

Author

Tengelmann, C, Kaußner, Y, Förster, C, Lunden, L, Wildermuth, R, Zang, N, Eidenschink, C, Erdmann, K, Sellmann, S, Feil, E, Kutterer, C, Zolk, O, Hartung, K, Malzahn, U, Hügen, K, Heuschmann, P, Escales, C, Maetzler, W, Joos, S, Kaduszkiewicz, H, Gágyor, I, Tengelmann, C, Kaußner, Y, Förster, C, Lunden, L, Wildermuth, R, Zang, N, Eidenschink, C, Erdmann, K, Sellmann, S, Feil, E, Kutterer, C, Zolk, O, Hartung, K, Malzahn, U, Hügen, K, Heuschmann, P, Escales, C, Maetzler, W, Joos, S, Kaduszkiewicz, H, and Gágyor, I

Published
2023

4. Planung einer Interventionsstudie nach Arzneimittelgesetz in der Allgemeinmedizin: Erkenntnisse aus PreVitaCOV

Author

Lunden, L, Tengelmann, C, Kaußner, Y, Kutterer, C, Wildermuth, R, Zang, N, Eidenschink, C, Erdmann, K, Sellmann, S, Feil, E, Zolk, O, Malzahn, U, Hügen, K, Heuschmann, P, Escales, C, Maetzler, W, Joos, S, Kaduszkiewicz, H, Gágyor, I, Förster, C, Lunden, L, Tengelmann, C, Kaußner, Y, Kutterer, C, Wildermuth, R, Zang, N, Eidenschink, C, Erdmann, K, Sellmann, S, Feil, E, Zolk, O, Malzahn, U, Hügen, K, Heuschmann, P, Escales, C, Maetzler, W, Joos, S, Kaduszkiewicz, H, Gágyor, I, and Förster, C

Published
2023

5. Platin-related Hearing Loss: Further Results from PanCareLIFE

Author

Parfitt, R, Matulat, P, Byrne, J, Langer, T, Deuster, D, Hesping, A, Clemens, E, Kaatsch, P, Grabow, D, O'Brien, K, Kaiser, M, Spix, C, Kremer, LC, van Dulmen-den Broeder, E, Calaminus, G, Baust, K, Kuehni, C, Weiss, A, Strebel, S, Kuonen, R, Elsner, S, Haupt, R, Garré, ML, Kepak, T, Kapakova, K, Falck Winther, J, Kenborg, L, Rechnitzer, C, Hasle, H, Kruseova, J, Luks, A, Lackner, H, Beilack, S, Hecker-Nolting, S, Beck, JD, van den Heuvel-Eibrink, M, Zolk, O, am Zehnhoff-Dinnesen, A, PanCareLIFE Consortium, Parfitt, R, Matulat, P, Byrne, J, Langer, T, Deuster, D, Hesping, A, Clemens, E, Kaatsch, P, Grabow, D, O'Brien, K, Kaiser, M, Spix, C, Kremer, LC, van Dulmen-den Broeder, E, Calaminus, G, Baust, K, Kuehni, C, Weiss, A, Strebel, S, Kuonen, R, Elsner, S, Haupt, R, Garré, ML, Kepak, T, Kapakova, K, Falck Winther, J, Kenborg, L, Rechnitzer, C, Hasle, H, Kruseova, J, Luks, A, Lackner, H, Beilack, S, Hecker-Nolting, S, Beck, JD, van den Heuvel-Eibrink, M, Zolk, O, am Zehnhoff-Dinnesen, A, and PanCareLIFE Consortium

Abstract

Background: Cisplatin and Carboplatin are widely-used in paediatric cancer treatment. Sensorineural hearing loss (SNHL) is one long-term side-effect. This study utilises a larger sample than previous research in order to investigate risk-factors for platin-related ototoxicity.Material and methods: Retrospective audiological and treatment data of 997 children and adolescents were gathered with the involvement of 18 pan-European institutions in 7 different countries as part of the PanCareLIFE consortium. Prior hearing loss was excluded. Conductive hearing losses were excluded where identified.Results: Prevalence rates of clinically-significant hearing loss (=> 2b Münster Classification) after treatment were 49 % (Cisplatin) and 15 % (Carboplatin). Where Cisplatin was administered prior to Carboplatin, prevalence rose to 76 %. Frequencies in the high and extended high-frequency range were predominantly affected, with mean threholds between 25-35 dB HL. Mean thresholds at frequencies below 3 kHz remained lower than 20 dB HL. No significant air-bone gap was apparent.50 % of clinically-significant hearing losses began within 3 years of start of treatment (Kaplan-Meier analysis). No significant difference in time-to-onset at different frequencies within the standard range was found. Further analyses, including multifactorial analysis to account for platin doses, presence of cranial radiotherapy, age and date of diagnosis will be conducted.Discussion: Analysis of this large sample was able to confirm the significant risk of SNHL posed by platin-based chemotherapeutics. Some quantitative and qualitative variation were present in this multi-centre retrospective dataset.Conclusion: This large sample confirms that platin-based chemotherapeutics, especially cisplatin, pose a significant risk of SNHL and underlines the necessity of audiological monitoring during and after end of chemotherapy.Acknowledgement: This work was supported by the PanCareLIFE consortium that has received

Published
2023

6. Prednisolon und Vitamin B1, B6 und B12 bei Post-COVID (PreVitaCOV) – eine randomisierte placebo-kontrollierte Pilotstudie in der Allgemeinmedizin

Author

Förster, C, Kaußner, Y, Tengelmann, C, Lunden, L, Eidenschink, C, Erdmann, K, Sellmann, S, Feil, E, Zolk, O, Malzahn, U, Hügen, K, Heuschmann, PU, Joos, S, Kaduszkiewicz, H, and Gágyor, I

Subjects
ddc: 610, Medicine and health
Abstract

Hintergrund: Eine relevante Anzahl von Patient:innen leidet nach einer Infektion mit SARS-CoV-2 weiterhin unter Beschwerden, die bei Fehlen anderer Ursachen ab einer Dauer von drei Monaten als Post-COVID bezeichnet werden und für die unterschiedliche pathophysiologische Ursachen diskutiert werden. [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Published
2022
Full Text
View/download PDF

7. Favourable tolerability in phase 1 study of CUSP9v3 (NCT02770378) in recurrent glioblastoma

Author

Halatsch, ME, Kast, R, Karpel-Massler, G, Mayer, B, Zolk, O, Schmitz, B, Scheuerle, A, Maier, L, Bullinger, L, Mayer-Steinacker, R, Schmidt, C, Zeiler, K, Elshaer, Z, Panther, P, Schmelzle, B, Hallmen, A, Dwucet, A, Siegelin, MD, Westhoff, MA, Beckers, K, Bouche, G, and Heiland, T

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Objective: In an attempt to address the variety and ever-shifting array of growth-promoting pathways glioblastomas (GB) use to thrive and circumvent our treatment efforts, we developed a nine repurposed drug regimen, CUSP9v3, designed to be given with temozolomide at 40 mg/m2/d. When conceptualizing[for full text, please go to the a.m. URL], 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Published
2021
Full Text
View/download PDF

8. 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

Perk, M.E.M. van der, Broer, L., Yasui, Y., Robison, L.L., Hudson, M.M., Laven, J. S. E., Pal, H.J. van der, Tissing, W.J., Versluys, B., Bresters, D., Kaspers, G.J., Vries, A.C.M. de, Lambalk, C.B., Overbeek, A., Loonen, J.J., Beerendonk, C.C.M., Byrne, J., Berger, C., Clemens, E., Dirksen, U., Winther, J. Falck, Fosså, S.D., Grabow, D., Muraca, M., Kaiser, M., Kepák, T., Kruseova, J., Modan-Moses, D., Spix, C., Zolk, O., Kaatsch, P., Krijthe, J.H., Kremer, L.C., Brooke, R.J., Baedke, J.L., Schaik, R.H. van, Anker, J.N. van den, Uitterlinden, A.G., Bos, A.M., Leeuwen, F.E. van, Dulmen-den Broeder, E. van, Kooi, A.L. Van der, Heuvel-Eibrink, M.M. van den, PanCare, L.C. On Behalf Of Th, Perk, M.E.M. van der, Broer, L., Yasui, Y., Robison, L.L., Hudson, M.M., Laven, J. S. E., Pal, H.J. van der, Tissing, W.J., Versluys, B., Bresters, D., Kaspers, G.J., Vries, A.C.M. de, Lambalk, C.B., Overbeek, A., Loonen, J.J., Beerendonk, C.C.M., Byrne, J., Berger, C., Clemens, E., Dirksen, U., Winther, J. Falck, Fosså, S.D., Grabow, D., Muraca, M., Kaiser, M., Kepák, T., Kruseova, J., Modan-Moses, D., Spix, C., Zolk, O., Kaatsch, P., Krijthe, J.H., Kremer, L.C., Brooke, R.J., Baedke, J.L., Schaik, R.H. van, Anker, J.N. van den, Uitterlinden, A.G., Bos, A.M., Leeuwen, F.E. van, Dulmen-den Broeder, E. van, Kooi, A.L. Van der, Heuvel-Eibrink, M.M. van den, and PanCare, L.C. On Behalf Of Th

Abstract

Contains fulltext : 237733.pdf (Publisher’s version ) (Open Access), 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/m(2) 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 treatme

Published
2021

9. TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

Author

Meijer, A, Diepstraten, FA, Langer, T, Broer, L, Domingo, IK, Clemens, E, Uitterlinden, AG, de Vries, ACH, van Grotel, M, Vermeij, WP, Ozinga, RA, Binder, H, Byrne, J, van Dulmen-den Broeder, E, Garrè, ML, Grabow, D, Kaatsch, P, Kaiser, M, Kenborg, L, Falck-Winther, J, Rechnitzer, C, Hasle, H, Kepak, T, Kepakova, K, Tissing, WJE, van der Kooi, ALF, Kremer, LC, Kruseova, J, Pluijm, SMF, Kuehni, CF, van der Pal, H, Parfitt, R, Spix, C, Hesping, A, Deuster, D, Matulat, P, Calaminus, G, Hoetink, AE, Elsner, S, Gebauer, J, Haupt, R, Lackner, H, Blattmann, C, Neggers, SJCMM, Rassekh, SR, Wright, GEB, Brooks, B, Nagtegaal, AP, Drögemöller, BI, Ross, CJD, Bhavsar, AP, am Zehnhoff-Dinnesen, A, Carleton, BC, Zolk, O, van den Heuvel-Eibrink, M, Meijer, A, Diepstraten, FA, Langer, T, Broer, L, Domingo, IK, Clemens, E, Uitterlinden, AG, de Vries, ACH, van Grotel, M, Vermeij, WP, Ozinga, RA, Binder, H, Byrne, J, van Dulmen-den Broeder, E, Garrè, ML, Grabow, D, Kaatsch, P, Kaiser, M, Kenborg, L, Falck-Winther, J, Rechnitzer, C, Hasle, H, Kepak, T, Kepakova, K, Tissing, WJE, van der Kooi, ALF, Kremer, LC, Kruseova, J, Pluijm, SMF, Kuehni, CF, van der Pal, H, Parfitt, R, Spix, C, Hesping, A, Deuster, D, Matulat, P, Calaminus, G, Hoetink, AE, Elsner, S, Gebauer, J, Haupt, R, Lackner, H, Blattmann, C, Neggers, SJCMM, Rassekh, SR, Wright, GEB, Brooks, B, Nagtegaal, AP, Drögemöller, BI, Ross, CJD, Bhavsar, AP, am Zehnhoff-Dinnesen, A, Carleton, BC, Zolk, O, and van den Heuvel-Eibrink, M

Abstract

Background: Ototoxicity (hearing loss, tinnitus and/or vertigo) is a serious adverse event of cisplatin treatment in children with cancer. The heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. This study investigated the association between carriership of novel single nucleotide polymorphisms (SNPs) and cisplatin-induced hearing loss (CIHL) in childhood cancer patients.Material and methods: The discovery cohort included cisplatin treated, non-cranial irradiated pediatric cancer patients within the European PanCareLIFE (PCL) study (N=390). CIHL at end of cancer treatment was defined as Muenster grade >=2b, assessed by pure tone audiometry. DNA was genotyped using the Infinium© Global Screening Array. Logistic regression models were applied including age at diagnosis, sex, cisplatin total cumulative dose and principal components 1-4, assuming an additive effect of the minor allele. Replication of the findings was performed in two independent, similarly treated cohorts (N=192 and N=188). Functional validation experiments in cultured human HeLa cell lines were performed to determine the effect of knockdown of the SNPs nearest identified gene on cisplatin-induced toxicity.Results: In the PCL discovery cohort, 8 SNPs reached a suggestive significance of P<1.0x10-5. One variant (rs893507) within the TCERG1L gene showed evidence of replication (P=0.01) in the Canadian first replication cohort. Analysis in the PCL second replication cohort confirmed this finding (P=1.0x10-4). The combined analysis showed that carriership of the C-allele of this newly discovered variant increases the odds of CIHL with 3.11-fold (P=5.3x10-10, 95% CI 2.2-4.5). Modulating TCERG1L expression significantly altered cell viability in response to cisplatin treatment, where TCERG1L overexpression and silencing protected and sensitized cells to cisplatin toxicity, respectively.Discussion: Children with cancer who carry a variant in the TCERG1L g

Published
2021

10. TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

Author

Meijer, A. J.M., Diepstraten, F. A., Langer, T., Broer, L., Domingo, I. K., Clemens, E., Uitterlinden, A. G., de Vries, A. C.H., van Grotel, M., Vermeij, W. P., Ozinga, R. A., Binder, H., Byrne, J., van Dulmen-den Broeder, E., Garrè, M. L., Grabow, D., Kaatsch, P., Kaiser, M., Kenborg, L., Winther, J. F., Rechnitzer, C., Hasle, H., Kepak, T., Kepakova, K., Tissing, W. J.E., van der Kooi, A.L.F. (Anne-Lotte), Kremer, L. C.M., Kruseova, J., Pluijm, S. M.F., Kuehni, C. E., van der Pal, H. J.H., Parfitt, R., Spix, C., Tillmanns, A., Deuster, D., Matulat, P., Calaminus, G., Hoetink, A. E., Elsner, S., Gebauer, J., Lackner, H., Haupt, R., Blattmann, C., Neggers, S. J.C.M.M., Rassekh, Sharad R., Wright, G.E.B., Brooks, B., Nagtegaal, A. P., Drögemöller, B.I., Ross, C.J.D., Bhavsar, A.P., am Zehnhoff-Dinnesen, A.G., Carleton, B.C., Zolk, O., van den Heuvel-Eibrink, M. M., Meijer, A. J.M., Diepstraten, F. A., Langer, T., Broer, L., Domingo, I. K., Clemens, E., Uitterlinden, A. G., de Vries, A. C.H., van Grotel, M., Vermeij, W. P., Ozinga, R. A., Binder, H., Byrne, J., van Dulmen-den Broeder, E., Garrè, M. L., Grabow, D., Kaatsch, P., Kaiser, M., Kenborg, L., Winther, J. F., Rechnitzer, C., Hasle, H., Kepak, T., Kepakova, K., Tissing, W. J.E., van der Kooi, A.L.F. (Anne-Lotte), Kremer, L. C.M., Kruseova, J., Pluijm, S. M.F., Kuehni, C. E., van der Pal, H. J.H., Parfitt, R., Spix, C., Tillmanns, A., Deuster, D., Matulat, P., Calaminus, G., Hoetink, A. E., Elsner, S., Gebauer, J., Lackner, H., Haupt, R., Blattmann, C., Neggers, S. J.C.M.M., Rassekh, Sharad R., Wright, G.E.B., Brooks, B., Nagtegaal, A. P., Drögemöller, B.I., Ross, C.J.D., Bhavsar, A.P., am Zehnhoff-Dinnesen, A.G., Carleton, B.C., Zolk, O., and van den Heuvel-Eibrink, M. M.

Abstract

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Published
2021

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

Author

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

Abstract

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Published
2020
Full Text
View/download PDF

12. 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

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

Author

Tillmanns, A, Parfitt, R, Matulat, P, Abdel-Kahaar, E, Maier, L, Zolk, O, Elsner, S, Wolschon, EM, Kuehni, CE, Kuonen, R, Weiss, A, Garré, ML, Kepak, T, Kepakova, K, Kruseova, J, Luks, A, Falck Winther, J, Kenborg, L, Lackner, H, Bielack, S, van den Heuvel-Eibrink, M, Calaminus, G, Baust, K, Beck, J, Kremer, L, Clemens, E, Langer, T, am Zehnhoff-Dinnesen, A, and PanCareLIFE consortium

Subjects
ddc: 610
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 markers in a large non-selected pediatric population of cancer survivors who had been treated with cisplatin and/or carboplatin.Materials and Methods: As a part of the PanCareLIFE study, the ototoxicity study included 2,696 survivors from 7 European countries treated with cisplatin and/or carboplatin for childhood cancer, resulting in the largest clinical European cohort assembled for this late-effect study. Hearing loss was audiologically classified using the Münster Classification. Three groups were defined, i.e., no hearing loss, minor hearing loss, and clinically relevant hearing loss. Patients were genotyped for single nucleotide polymorphisms (SNPs) in 7 candidate genes. Genetic association analyses were performed considering non-genetic covariates.Results: 900 patients were included in the final genetic analysis. Multinomial logistic regression was performed to model the relationship between the predictors and membership in the hearing loss group. The model explained 25% of the variance in hearing loss and correctly classified 58% of cases. Significant unique contributions were made by SLC22A2 rs316019 (P=0.017), age at the start of platinum treatment (P=1.46x10-17), cranial radiation (P=5.42x10-6), and the cumulative dose of cisplatin (P=5.86x10-19). Addition of the rs316019 genetic marker to the non-genetic risk factors (age, dose, cranial radiation) improved the area under the ROC curve only marginally (0.731 vs. 0.730).Discussion: Our study confirmed one potential genetic marker, rs316019 in SLC22A2. Its predictive value, however, is low.Conclusion: Due to the heterogeneity of results from genetic association studies performed so far, the evidence seems not yet sufficient to recommend screening for specific markers. Advances in the understanding of the pathophysiologic mechanisms of cisplatin-induced ototoxicity, as well as future genome-wide association studies, may help identify suitable genetic markers.Acknowledgement: This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030.

Published
2019

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

Author

Parfitt, R, Tillmanns, A, Matulat, P, Deuster, D, Elsner, S, Wolschon, EM, Kuehni, CE, Kuonen, R, Weiss, A, Garré, ML, Kepak, T, Kepakova, K, Kruseova, J, Luks, A, Falck Winther, J, Kenborg, L, Lackner, H, Bielack, S, van den Heuvel-Eibrink, M, Calaminus, G, Baust, K, Beck, J, Kremer, L, Clemens, E, Langer, T, Zolk, O, and am Zehnhoff-Dinnesen, A

Subjects
ddc: 610
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 of the PanCareLIFE consortium, we gathered audiological data from 13 pan-European clinics. Eligible patients were 20 dB HL at any frequency).A total of 2,696 patients with 10,320 audiograms from various stages of cancer treatment were obtained. Audiometric data were quality-checked and classified (Münster and SIOP classifications) and 736 patients with sufficient data were phenotyped. A logistic regression investigated the likelihood of developing a hearing loss >=Münster 2b (thresholds >40 dB HL at >=4 kHz) after treatment given age, gender, cisplatin dose and cranial irradiation.Results: 48.2% of 1,385 patients with a post-treatment audiogram had clinically-relevant hearing loss (defined as >=Münster 2b) after platin treatment.Children 15 years (odds ratio 2.7, 95% CI 1.5-4.9, p=0.0006). Patients with a cumulative cisplatin dose >450 mg/m2 were more likely to develop hearing loss than those treated with carboplatin alone (OR 12.5, 95% CI 6.8-23.0, p=3.7x10-16). Treatment with cranial irradiation was more likely to lead to hearing loss than without (OR 4.5, 95% CI 3.0-6.7, p=7.2x10-13).Discussion: This is the first study of platin ototoxicity with such a large sample size. The results support tendencies found in previous studies with smaller groups. The high risk groups identified here must be monitored regularly for ototoxicity. Further detailed analyses into audiological changes and possible pharmacogenetic confounders are planned.Conclusion: 48% of patients treated with cisplatin develop clinically-relevant hearing loss. Age

Published
2019

25. Interim results from a proof-of-concept clinical trial assessing the safety of the coordinated undermining of survival paths by 9 repurposed drugs (version 3) combined with metronomic temozolomide (CUSP9v3) protocol for recurrent glioblastoma

Author

Halatsch, ME, Kast, RE, Karpel-Massler, G, Schmitz, B, Zolk, O, Bullinger, L, Mayer-Steinacker, R, Maier, L, Scheuerle, A, Mayer, B, Schmidt, C, Zeiler, K, Elshaer, Z, Awad, F, Panther, P, Schmelzle, B, Beckers, K, Siegelin, MD, Westhoff, MA, Wirtz, CR, Bouche, G, and Heiland, T

Subjects
ddc: 610, 610 Medical sciences, Medicine, neoplasms
Abstract

Objective: Despite refinements of neurosurgical techniques and emerging adjuvant therapies, patients with recurrent glioblastoma continue to face a dismal prognosis. We report interim results of a prospective clinical trial (NCT02770378) evaluating a protocol of 9 repurposed drugs (aprepitant, minocyclin,[for full text, please go to the a.m. URL], 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Published
2019
Full Text
View/download PDF

26. Genetic determinants of ototoxicity during and after childhood cancer treatment: Protocol for the pancarelife study

Author

Clemens, E. (Eva), Meijer, A.J.M. (Annelot J.M.), Broer, L. (Linda), Langer, T. (Thomas), Kooi, A.L.F. (Anne-Lotte) van der, Uitterlinden, A.G. (André), Vries, A.C.H. (Andrica) de, Kuehni, C. (Claudia), Garrè, M.L. (Maria L.), Kepak, T. (Tomas), Kruseova, J. (Jarmila), Winther, J.F. (Jeanette F.), Kremer, L.C.M. (Leontien), Dulmen-den Broeder, E. (Eline) van, Tissing, W.J.E. (Wim), Rechnitzer, C. (Catherine), Kenborg, L. (Line), Hasle, H. (Henrik), Grabow, D. (Desiree), Parfitt, R. (Ross), Binder, H. (Harald), Carleton, B.C. (Bruce), Byrne, J. (Julianne), Kaatsch, P. (Peter), Zehnhoff-Dinnesen, A. (Antoinetteam), Zolk, O. (Oliver), Heuvel-Eibrink, M.M. (Marry) van den, Clemens, E. (Eva), Meijer, A.J.M. (Annelot J.M.), Broer, L. (Linda), Langer, T. (Thomas), Kooi, A.L.F. (Anne-Lotte) van der, Uitterlinden, A.G. (André), Vries, A.C.H. (Andrica) de, Kuehni, C. (Claudia), Garrè, M.L. (Maria L.), Kepak, T. (Tomas), Kruseova, J. (Jarmila), Winther, J.F. (Jeanette F.), Kremer, L.C.M. (Leontien), Dulmen-den Broeder, E. (Eline) van, Tissing, W.J.E. (Wim), Rechnitzer, C. (Catherine), Kenborg, L. (Line), Hasle, H. (Henrik), Grabow, D. (Desiree), Parfitt, R. (Ross), Binder, H. (Harald), Carleton, B.C. (Bruce), Byrne, J. (Julianne), Kaatsch, P. (Peter), Zehnhoff-Dinnesen, A. (Antoinetteam), Zolk, O. (Oliver), and Heuvel-Eibrink, M.M. (Marry) van den

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 identi

Published
2019
Full Text
View/download PDF

27. 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

28. Incidence and course of ototoxic hearing loss in a big European cohort of childhood cancer patients – subproject of PanCareLIFE

Author

Tillmanns, A, Parfitt, R, Matulat, P, Deuster, D, Clemens, E, Langer, T, Bielack, S, van Dulmen-den Broeder, E, Kuehni, C, Lackner, H, Kepak, T, Kruseova, J, Haupt, R, Falck-Winther, J, Kremer, L, Calaminus, G, Broer, L, Uitterlinden, A, Zolk, O, Van den Heuvel-Eibrink, M, Byrne, J, Kaatsch, P, and am Zehnhoff-Dinnesen, A

Subjects
ddc: 610, otorhinolaryngologic diseases, 610 Medical sciences, Medicine
Abstract

Background Ototoxicity is a common side effect after platin chemotherapy and existing studies are limited due to small cohorts and a variety of confounding factors [ref:1], [ref:2]. Therefore, studies that enrolled greater numbers of patients will help us to learn more about incidence[for full text, please go to the a.m. URL], 4. Dreiländertagung D-A-CH, 35. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP)

Published
2018
Full Text
View/download PDF

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

Author

Kooi, A.L.F. (Anne-Lotte) van der, Clemens, E. (Eva), Broer, L. (Linda), Zolk, O. (Oliver), Byrne, J. (Julianne), Campbell, H. (Helen), Berg, M.H. (Marleen) van den, Berger, C. (Claire), Calaminus, G. (Gabriele), Dirksen, U. (Uta), Winther, J.F. (Jeanette Falck), Fossa, S.D. (Sophie), Grabow, D. (Desiree), Haupt, R. (Riccardo), Kaiser, M. (Melanie), Kepak, T. (Tomas), Kremer, L.C.M. (Leontien), Kruseova, J. (Jarmila), Modan-Moses, D. (Dalit), Ranft, A. (Andreas), Spix, C. (Claudia), Kaatsch, P. (Peter), Laven, J.S.E. (Joop), Dulmen-den Broeder, E. (Eline) van, Uitterlinden, A.G. (André G), Heuvel-Eibrink, M.M. (Marry) van den, Kooi, A.L.F. (Anne-Lotte) van der, Clemens, E. (Eva), Broer, L. (Linda), Zolk, O. (Oliver), Byrne, J. (Julianne), Campbell, H. (Helen), Berg, M.H. (Marleen) van den, Berger, C. (Claire), Calaminus, G. (Gabriele), Dirksen, U. (Uta), Winther, J.F. (Jeanette Falck), Fossa, S.D. (Sophie), Grabow, D. (Desiree), Haupt, R. (Riccardo), Kaiser, M. (Melanie), Kepak, T. (Tomas), Kremer, L.C.M. (Leontien), Kruseova, J. (Jarmila), Modan-Moses, D. (Dalit), Ranft, A. (Andreas), Spix, C. (Claudia), Kaatsch, P. (Peter), Laven, J.S.E. (Joop), Dulmen-den Broeder, E. (Eline) van, Uitterlinden, A.G. (André G), and Heuvel-Eibrink, M.M. (Marry) van den

Abstract

BACKGROUND: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment as the primary outcome in CCS.METHODS: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent C

Published
2018
Full Text
View/download PDF

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

Author

Clemens, E. (E.), Kooi, A.L.F. (Anne-Lotte) van der, Broer, L. (Linda), Dulmen-den Broeder, E. (Eline) van, Visscher, H. (H.), Kremer, L.C.M. (Leontien), Tissing, W.J.E. (Wim), Loonen, J.J. (Jacqueline), Ronckers, C.M. (Cécile), Pluijm, S.M.F. (Saskia), Neggers, S.J.C.M.M. (Bas), Zolk, O. (Oliver), Langer, T. (Thomas), Zehnhoff-Dinnesen, A.A. (A. am), Wilson, C.L. (C. L.), Hudson, M.M. (Melissa), Carleton, B.C. (Bruce), Laven, J.S.E. (Joop), Uitterlinden, A.G. (André), Heuvel-Eibrink, M.M. (Marry) van den, Clemens, E. (E.), Kooi, A.L.F. (Anne-Lotte) van der, Broer, L. (Linda), Dulmen-den Broeder, E. (Eline) van, Visscher, H. (H.), Kremer, L.C.M. (Leontien), Tissing, W.J.E. (Wim), Loonen, J.J. (Jacqueline), Ronckers, C.M. (Cécile), Pluijm, S.M.F. (Saskia), Neggers, S.J.C.M.M. (Bas), Zolk, O. (Oliver), Langer, T. (Thomas), Zehnhoff-Dinnesen, A.A. (A. am), Wilson, C.L. (C. L.), Hudson, M.M. (Melissa), Carleton, B.C. (Bruce), Laven, J.S.E. (Joop), Uitterlinden, A.G. (André), and Heuvel-Eibrink, M.M. (Marry) van den

Abstract

Introduction: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. Methods: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. Results: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. Conclusion: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample coll

Published
2018
Full Text
View/download PDF

31. 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

32. 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

34. 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
Full Text
View/download PDF

35. Transportproteine in Plattenepithelkarzinomen des Kopf-Hals-Bereichs

Author

Traxdorf, M, Zolk, O, Fromm, M, Zenk, J, and Iro, H

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Für einige Arten solider Tumore wurde gezeigt, dass der Expressionsgrad bestimmter zellulärer Transportproteine in den Karzinomzellen deren Zytostatika-Sensitivität (Multidrug-Resistenz), die Tumorangiogenese sowie antiapoptotische Mechanismen beeinflussen kann. Unklar ist, welche spezifischen[for full text, please go to the a.m. URL], 82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie

Published
2011
Full Text
View/download PDF

36. Effects of quinapril, losartan and hydralazine on cardiac hypertrophy and beta-adrenergic neuroeffector mechanisms in transgenic (mREN2)27 rats

Author

Zolk, O, Flesch, M, Schnabel, P, Teisman, AC, Pinto, YM, van Gilst, WH, Paul, M, Bohm, M, Other departments, and Cardiovascular Centre (CVC)

Subjects
ANGIOTENSIN-CONVERTING ENZYME, G-protein, ADENYLATE-CYCLASE, INHIBITION, PROTEIN, renin transgenic rat, NEUROPEPTIDE-Y, CELLS, HEART, angiotensin II antagonist, adenylyl cyclase, ACE-inhibitor, MOUSE REN-2 GENE, SYSTEM, HYPERTENSIVE RATS
Abstract

1 Desensitization of the myocardial beta-adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an angiotensin converting enzyme (ACE)-inhibitor, an AT(1)-receptor antagonist and a direct vasodilator on blood pressure, cardiac hypertrophy and the beta-adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension with cardiac hypertrophy. 2 Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT(1)-receptor antagonist losartan (10 mg kg(-1)), the ACE-inhibitor quinapril (15 mg kg(-1)) and the direct vasodilator hydralazine (30 mg kg(-1)). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3 TG(mREN2)27-rats were characterized by arterial hypertension (TG 194 +/- 3.2 mmHg vs SD 136 +/- 2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3 +/- 0.3 vs SD 3.0 +/- 0.1 mg g(-1) body weight), decreased myocardial neuropeptide Y (NPY) concentrations (TG 1143 +/- 108 vs SD 1953 +/- 134 pg g(-1) wet weight), reduced beta-adrenoceptor densities (TG 51.1 +/- 1.9 vs SD 63.4 +/- 3.7 fmol mg(-1)) as assessed by [I-125]-cyanopindolol binding studies, and increased G(i alpha)-activities (TG 4151 +/- 181 vs SD 3169 +/- 130 densitometric units) as assessed by pertussis toxin catalyzed [P-32]-ADP-ribosylation. Downregulation of beta-adrenoceptors and increased G(i alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylyl cyclase activity. Catalyst activity as determined by forskolin plus Mn2+ co-stimulation of adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4 Losartan and quinapril significantly restored systolic blood pressures, left ventricular weights, beta-adrenoceptor densities, myocardial neuropeptide Y-concentrations, adenylyl cyclase activities and G(i alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of quinapril- and losartan-treatment. In contrast, hydralazine had only minor effects on blood pressure reduction, regression of left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5 In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT(1)-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive cardiomyopathy.

Published
1998

Catalog

Books, media, physical & digital resources
See catalog results