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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

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

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

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

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 (rs893507) 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 (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10−10, OR 3.11, 95% CI 2.2–4.5). 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.

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 (rs893507) 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 (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10−10, OR 3.11, 95% CI 2.2–4.5). 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.

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.

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.

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 <18 years old at diagnosis, underwent treatment with cisplatin or carboplatin and had no evidence of pre-treatment hearing loss (>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 <5 years old were more likely to develop hearing loss than those >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 dev

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

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

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

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 <18 years old at diagnosis, underwent treatment with cisplatin or carboplatin and had no evidence of pre-treatment hearing loss (>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 <5 years old were more likely to develop hearing loss than those >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 dev