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

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.

Overweight, obesity and adiposity in survivors of childhood brain tumours: a systematic review and meta-analysis.

Survivors of childhood brain tumours (SCBT) have increased cardiometabolic risks, but the determinants of these risks are unclear. This systematic review aims to compare the prevalence of overweight and obesity as well as adiposity measures between SCBT and non-cancer controls. The PubMed, EMBASE, MEDLINE, CINAHL and the Cochrane Library databases were searched. The primary outcomes were the prevalence of overweight and obesity based on body mass index. The secondary outcomes were adiposity measures including percent fat mass, waist-to-hip and waist-to-height ratios. Forty-one studies were included in the meta-analysis. The prevalence of overweight and obesity combined was similar between overall SCBT, SCBT excluding craniopharyngioma and non-cancer controls (42.6%, 95% CI 30.1-55.1 vs. 31.7%, 95% CI 20.4-43.0 vs. 40.4%, 95% CI 34.0-46.8). We also found that SCBT have higher percent fat mass (mean difference 4.1%, 95% CI 2.0-6.1), waist-to-hip ratio (mean difference 0.07, 95% CI 0.02-0.13) and waist-to-height ratio (mean difference 0.06, 95% CI 0.01-0.10) than non-cancer controls. We conclude that SCBT have similar overweight and obesity distribution but higher adiposity than non-cancer controls. More studies were needed to explore the determinants of adiposity and its contribution to cardiometabolic outcomes in SCBT.

The effectiveness of interventions to treat hypothalamic obesity in survivors of childhood brain tumours: a systematic review.

BACKGROUND: Survivors of childhood brain tumours (SCBT) are at risk of type 2 diabetes and cardiovascular diseases. Obesity is a major driver of cardiometabolic diseases in the general population, and interventions that tackle obesity may lower the risk of these chronic diseases. The goal of this systematic review was to summarize current evidence for the presence of interventions to manage obesity, including hypothalamic obesity, in SCBT. METHODS: The primary outcome of this review was the body mass index z-score change from baseline to the end of the intervention and/or follow-up. Literature searches were conducted in PsycINFO, CINAHL, the Cochrane Library, Medline, SPORTDiscus, EMBASE and PubMed. Two reviewers completed study evaluations independently. RESULTS: Eleven publications were included in this systematic review (lifestyle intervention n = 2, pharmacotherapy n = 6 and bariatric surgery n = 3). While some studies demonstrated effectiveness of interventions to manage obesity in SCBT and alter markers of obesity and cardiometabolic risk, the evidence base was limited and of low quality, and studies focused on hypothalamic obesity. We conclude that there is urgent need to conduct adequately powered trials of sufficient duration, using existing and novel therapies to manage obesity, reduce the burden of cardiometabolic disorders and improve outcomes in SCBT.

Genetic markers of cisplatin-induced hearing loss in children.

This journal recently published a Commentary by Ratain and colleagues at the University of Chicago that criticizes our work on cisplatin-induced hearing loss in children. It is unfortunate that neither the authors nor the editors of Clinical Pharmacology & Therapeutics corresponded with us to provide an earlier opportunity to address these questions. Here we correct the authors' inaccuracies and provide additional analyses that further strengthen our published findings.

Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent.

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.

Reclassification of ICD-9 Codes into Meaningful Categories for Oncology Survivorship Research.

Background. The International Classification of Disease, ninth revision (ICD-9) is designed to code disease into categories which are placed into administrative databases. These databases have been used for epidemiological studies. However, the categories used in the ICD9-codes are not always the most effective for evaluating specific diseases or their outcomes, such as the outcomes of cancer treatment. Therefore a re-classification of the ICD-9 codes into new categories specific to cancer outcomes is needed. Methods. An expert panel comprised of two physicians created broad categories that would be most useful to researchers investigating outcomes and morbidities associated with the treatment of cancer. A Senior Data Coordinator with expertise in ICD-9 coding, then joined this panel and each code was re-classified into the new categories. Results. Consensus was achieved for the categories to go from the 17 categories in ICD-9 to 39 categories. The ICD-9 Codes were placed into new categories, and subcategories were also created for more specific outcomes. The results of this re-classification is available in tabular form. Conclusions. ICD-9 codes were re-classified by group consensus into categories that are designed for oncology survivorship research. The novel re-classification system can be used by those involved in cancer survivorship research.

Functional deterioration following placode untethering in myelomeningocele.

Placode untethering in myelomeningocele patients can result in improvement and/or stabilization of neurological function, spinal curvature and pain. This paper reviews the outcome of untethering procedures in 24 patients to determine the frequency of subsequent functional deterioration. Decreased range of movement, joint stiffness and changes in muscle tone were the commonest indications for surgical intervention, occurring in 15 patients. Untethering resulted in improvement in 8 patients, stabilization of progression in 6 and continued deterioration in 1 patient. Two patients previously untroubled with spasticity became symptomatic within 3 months of the procedure. Changes in ambulation were present preoperatively in 9 patients. Stabilization was observed in 4 and improvement in 5. One of the patients, who had improved, deteriorated during the 1st year of follow-up. Alterations in bladder capacity and continence occurred in 7 patients. Improvement was seen in 2 patients, deterioration in 2 and no change in 3. Of the patients who improved, 1 subsequently deteriorated again within the 2nd postoperative year. Of those patients who had stable bladder function preoperatively, 6 subsequently deteriorated despite untethering. Pain was a less frequent symptom, occurring in 6 patients. Six patients became pain-free within 3 months of untethering. Two patients who did not have pain preoperatively had pain at the operative site persisting for up to 3 months postoperatively. Of the 20 patients having a single untethering procedure to date, 11 have further symptoms that can be attributed to retethering.