Rachel Conyers

Liposarcoma: Molecular Genetics and Therapeutics

Sarcomas are a group of heterogeneous tumours with varying genetic basis. Cytogenetic abnormalities range from distinct genomic rearrangements such as pathognomonic translocation events and common chromosomal amplification or loss, to more complex rearrangements involving multiple chromosomes. The different subtypes of liposarcoma are spread across this spectrum and constitute an interesting tumour type for molecular review. This paper will outline molecular pathogenesis of the three main subtypes of liposarcoma: well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Both the molecular basis and future avenues for therapeutic intervention will be discussed.

Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis.

PURPOSE The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of individual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. PATIENTS AND METHODS Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. RESULTS After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P < .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P < .001). Children reported the highest rates of grade 3 or 4 neutropenia (P < .001) and thrombocytopenia (P < .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P < .001). CONCLUSION These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes.

Reproductive concerns of children and adolescents with cancer: challenges and potential solutions

The diagnosis of a potentially life-threatening cancer is one of the most traumatic events that can befall a young person and his or her family. However, fortunately, most young people will survive their cancer and its treatment and go on to lead a long and healthy life, with an appropriate expectation of being able to have their own genetic family. However, cancer treatment, including surgery, chemotherapy, and radiotherapy, can have temporary and permanent effects on fertility, including damage to the uterus and pituitary gland, and reduction, or obliteration, of gonadal function, with consequential loss of oocytes or spermatozoa, which may result in ovarian or testicular failure. As the gamete pool is nonrenewable, permanent gonadal failure precludes subsequent fertility with a patients own genetic material. Awareness and acknowledgement of the likely future fertility implications of cancer treatment is an essential part of any discussion about proposed therapies. Options for girls and young women include freezing mature oocytes and ovarian tissue, as well as attempting to protect the ovaries from the gonadotoxic effects of treatment. Options for boys and young men include semen collection and storage as well as testicular biopsy with freezing of testicular tissue or spermatozoa retrieved from the tissue. Fertility options can now be offered with increasing optimism about success and the provision of a genuine opportunity for having a family. While the initiation of cancer treatment is sometimes truly urgent, the opportunity for a detailed discussion about implications for fertility is of paramount importance for patients and their families and provides both reassurance and optimism about the future.

Inconsistencies and time delays in site-specific research approvals hinder collaborative clinical research in Australia

The aim of this study was to describe the time and documentation needed to gain ethics and governance approvals in Australian states with and without a centralised ethical review system.

Agitation and weight loss in an autistic boy.

Abstract:  An 11 year old boy with autism presented with a 2‐month history of agitated behaviour with associated weight loss. On examination he was wasted and distressed. He had severe hypoalbuminaemia. Gastrointestinal imaging revealed a gastric bezoar. At operation a large phytobezoar extending into the jejunum was identified and removed. Postoperatively he required intensive nutritional resuscitation and support, including treatment of multiple micronutrient deficiencies. Malnutrition is common in children with developmental disabilities, with a number of possible contributing factors. Gastric bezoar is a rare cause, which should be considered in mobile children who may engage in pica.

Do Australian adolescents' and young adults' experiences of cancer care influence their quality of life?

To examine the relationship between the cancer care experiences of adolescents and young adults (AYAs) and their quality of life.

Genetic determinants of anthracycline cardiotoxicity - ready for the clinic?

We read with great interest the thorough and informative review by Aminkeng et al. [4] addressing the possibility that genetic screening may reduce the rate of anthracyclineinduced cardiotoxicity (ACT). Predictors of anthracycline toxicity including genetic predisposing single nucleotide polymorphisms (SNPs) and biomarkers are lacking in the clinical setting. Therefore, the identification of reliable genetic predictors of ACT, as described by Aminkeng and colleagues [4], would be broadly welcomed as the beginning of personalised, genomic-based management of long-term cardiotoxicity. However, we contend that more evidence supporting the utility of these markers for patient stratification is required before clinical guidelines can be issued. Aminkeng and colleagues [4] describe a number of genetic variants and recommend that genomic testing for RARG rs2229774 (S427 L), SLC28A3 rs7853758 (L461 L) and UGT1A6 rs17863783 (V209 V) be performed for paediatric childhood cancer patients receiving doxorubicin or daunorubicin. Importantly, the evidence to support this is defined as “moderate evidence reflecting a reduced confidence in scientific evidence and expert opinion”. Moreover, these three genetic variants have only an association or correlation with the incidence of ACT within a particular patient cohort, and there is no functional validation of causation. The genetic variants of SLC28A3 rs7853758 and UGT1A6 rs17863783 in particular require further validation since neither alter protein-coding for these genes, and UGT1A6 rs17863783 is intronic in some alternate transcripts. There are other potential explanations for an apparent contribution to anthracycline cardiotoxicity including altered RNA splicing, or the SNP being representative of a haplotype that includes variants that do alter protein function [5, 6]. Neither SLC28A3 nor UGT1A6 variants create splice acceptor or donor sites and so do not result in alternate transcripts. Furthermore, we note that neither SLC28A3 nor UGT1A6 are expressed in the heart, which suggests that their contribution to cardiotoxicity is not related to direct effects in cardiac tissue. Without complete functional studies, the downstream effects of SLC28A3 and UGT1A6 synonymous SNPs and their clinical impact remains speculative. Care must be taken when determining the clinical significance and utility of these genetic variants. The mechanisms of anthracycline pharmacodynamics and metabolism are complex. We are concerned about clinical recommendations arising from these studies including the suggestions for longterm follow-up for high-, moderateand low-risk patients. More particularly, there is the potential for alteration of dosage scheduling based on insufficient genetic evidence. This could result in potentially under-dosing in patients with these alleles. Thus, whilst we strongly support the identification of genetic predictors of anthracycline toxicity, without sufficient validation of the functional effects of these variants, it is premature to suggest that patient care, particularly late effect screening and upfront changes in therapy, be considered. With the ever-reducing cost of large-scale genetic analysis British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 1141–1142 1141

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area.

Factors influencing the documentation of fertility-related discussions for adolescents and young adults with cancer

PURPOSE A cancer diagnosis and treatment may have significant implications for a young patients future fertility. Documentation of fertility-related discussions and actions is crucial to providing the best follow-up care, which may occur for many years post-treatment. This study examined the rate of medical record documentation of fertility-related discussions and fertility preservation (FP) procedures for adolescents and young adults (AYAs) with cancer in Australia. METHODS A retrospective review of medical records for 941 patients in all six Australian states. Patients were identified through population-based cancer registries (four states) and hospital admission lists (two states). Trained data collectors extracted information from medical records using a comprehensive data collection survey. Records were reviewed for AYA patients (aged 15-24 years at diagnosis), diagnosed with acute myeloid leukaemia, acute lymphoblastic leukaemia, central nervous system (CNS) tumours, soft tissue sarcomas (STS), primary bone cancer or Ewings family tumours between 2007 and 2012. RESULTS 47.2% of patients had a documented fertility discussion and 35.9% had a documented FP procedure. Fertility-related documentation was less likely for female patients, those with a CNS or STS diagnosis and those receiving high-risk treatments. In multivariable models, adult hospitals with an AYA focus were more likely to document fertility discussions (odds ratio[OR] = 1.60; 95%CI = 1.08-2.37) and FP procedures (OR = 1.74; 95%CI = 1.17-2.57) than adult hospitals with no AYA services. CONCLUSIONS These data provide the first national, population-based estimates of fertility documentation for AYA cancer patients in Australia. Documentation of fertility-related discussions was poor, with higher rates observed in hospitals with greater experience of treating AYA patients.

Chemotherapy related cardiotoxicity – Are Australian practitioners missing the point?

It has long been established that cardiotoxicity occurs as a result of exposure to certain chemotherapeutics, particularly anthracyclines. Historically, clinicians equate cardiotoxicity with a poor prognosis, in a small percentage of patients and deem long‐term surveillance as optional. Emerging evidence suggests that anthracycline cardiotoxicity (ACT) is a life‐long risk with an incidence approaching 20%.