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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

Purpose: The aims of patients’ radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5–104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI

The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days.

BackgroundThe aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days.MethodsForty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment.ResultsMedian age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%).ConclusionsTMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.

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Complete ependymoma resection ensures a better prognosis for children with this tumor, but the complete excision of infratentorial ependymomas involves serious risks. Second-look surgery for tumor remnants may be less harmful and enable complete removal. There is a potential, although still unclear, role for neoadjuvant chemotherapy in preparation for further surgery.