Nutrition screening, assessment, and intervention practices for children with cancer in Aotearoa, New Zealand.

OBJECTIVE: The purpose of this study was to investigate dietetic resources and current nutrition screening, assessment, and intervention practices in pediatric oncology centers in Aotearoa, New Zealand. METHODS: A national survey of the two specialist treatment centers and 14 shared care centers that provide care to childhood cancer patients in Aotearoa, New Zealand, was conducted. RESULTS: The two specialist treatment centers in Aotearoa, New Zealand, were the only centers with a dedicated dietetic oncology full-time equivalent resource; this full-time equivalent resource was devoted to inpatient care. Only 5 shared care centers (44%) had access to general pediatric dietetic support. Dietetic cover for outpatients or day-stay patients and use of standardized nutrition screening and assessment tools were limited. Weight and height were commonly measured, but there was inconsistency in the frequency and recording of measurements. Nutrition interventions, including nutrition education, oral nutrition support, enteral nutrition, and intravenous nutrition, were available within all centers but criteria for initiating support varied. Common barriers to providing nutrition interventions included staff resourcing and ad hoc referral pathways. Awareness of the relevance and clinical benefit of nutrition in pediatric oncology was low. Suggestions to improve nutrition screening, assessment, and intervention within Aotearoa, New Zealand, included the creation of standardized screening and referral criteria. CONCLUSIONS: Resource limitations and lack of nutritional screening and assessment prevent adequate nutritional intervention for children with cancer in Aotearoa, New Zealand. Akin to other high-income countries, there is a need to harmonize the management of nutritional challenges in children with cancer. This study provides a first step in establishing an evidence base to help support efforts to address this need in Aotearoa, New Zealand.

Understanding the patient and family experience of nutrition and dietetic support during childhood cancer treatment.

PURPOSE: This study aimed to understand the experience of families caring for a child with cancer in New Zealand (NZ) who received nutrition and dietetic support during cancer treatment and their preferences for the delivery, format, and timing of nutrition information. METHODS: Childhood cancer patients and their families (N = 21) participated in a mixed-methods study at a specialist paediatric oncology centre in Auckland, NZ. Before the semi-structured interview, participants completed a questionnaire capturing demographic, disease, and treatment characteristics of their child, their nutrition concerns, and their information needs. Quantitative data were described, and qualitative thematic analysis of the semi-structured interviews was performed using NVivo data analysis software. RESULTS: Eighty-six percent of participants indicated they had concerns about their child's nutrition during treatment. The most common concerns were anorexia, vomiting, and weight loss. While many were happy with the quality of the nutrition support received, one-third of the patients wanted more support. Four key themes emerged from the interviews: (1) patients experience significant and distressing nutrition challenges; (2) patients and families have mixed perceptions of EN; (3) there are gaps in the current nutrition support system for inpatients; and (4) a desire for more accessible nutrition support. CONCLUSION: Childhood cancer patients and families experience significant and distressing nutrition challenges during treatment. Standardising information given to patients and their families may optimise nutrition support for paediatric oncology patients and reduce the discordance between families and health professionals. Future implementation of a nutrition decision aid in this population is warranted.

BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience.

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.

Malignant Melanoma in Children and Adolescents Treated in Pediatric Oncology Centers: An Australian and New Zealand Children's Oncology Group (ANZCHOG) Study.

OBJECTIVES: Unlike adults, malignant melanoma in children and adolescents is rare. In adult melanoma, significant progress in understanding tumor biology and new treatments, including targeted therapies and immunotherapy have markedly improved overall survival. In sharp contrast, there is a paucity of data on the biology and clinical behavior of pediatric melanoma. We report a national case series of all pediatric and adolescent malignant melanoma presenting to ANZCHOG Childhood Cancer Centers in Australia and New Zealand. METHODS: A retrospective, descriptive, multi-center study was undertaken to identify patients less than 18 years of age treated for cutaneous malignant melanoma over a twenty-year period (1994 to 2014). Data on clinical characteristics, histopathology, and extent of disease, treatment and follow-up are described. RESULTS: A total of 37 cases of malignant melanoma were identified from all of the Australasian tertiary Childhood Cancer Centers. The median age was 10 years (range 1 month - 17 years). Clinically, the most common type of lesion was pigmented, occurring in sixteen (57%) patients, whilst amelanotic was seen in 7 patients (25%). In 11 (27.9%) the Breslow thickness was greater than 4mm. A total of 11 (29.7%) patients relapsed and 90% of these died of disease. Five-year event free survival (EFS) and overall survival were 63.2 (95% CI: 40.6 - 79.1) and 67.7% (95% CI: 45.1 - 82.6) respectively. CONCLUSION: Our data confirms that melanoma is a rare presentation of cancer to tertiary Australasian Childhood Cancer Centers with only 37 cases identified over two decades. Notably, melanoma managed in Childhood Cancer Centers is frequently at an advanced stage, with a high percentage of patients relapsing and the majority of these patients who relapsed died of disease. This study confirms previous clinical and prognostic information to support the early multidisciplinary management in Childhood Cancer Centers, in conjunction with expert adult melanoma centers, of this rare and challenging patient group.

Neuropsychological assessment of paediatric brain tumour survivors: Factors associated with assessment.

AIM: Paediatric brain tumour survivors are at increased risk of neurocognitive deficits that affect their education. The aim of this study was to assess the proportion of brain tumour survivors who historically received a neuropsychological assessment and examine the demographic and treatment-related variables associated with neuropsychological assessment. A further aim was to determine the number and treatment profile of brain tumour survivors who would benefit from neuropsychological assessment. METHODS: Data from the New Zealand Children's Cancer Registry including treatments received, was used to identify children treated for a brain tumour at Starship Children's Hospital between January 2009 and December 2015. Clinical records were examined for evidence of a neuropsychological assessment in the form of a written report. Logistic regression models were used to determine factors associated with receipt of an assessment. RESULTS: Of the 132 brain tumour survivors, 37 (28.0%) had evidence of a neuropsychological assessment in their clinical records. In adjusted analysis, children who were treated with all three of surgery, chemotherapy and radiotherapy (n = 38) were more likely to have had an assessment (odds ratio: 12.90; 95% confidence interval: 4.76-34.93) than children who had either no treatment, chemotherapy alone, surgery alone or chemotherapy and surgery (n = 73). Treatment with radiotherapy alone or with either chemotherapy or surgery (n = 21) was not significantly associated with receipt of assessment (odds ratio = 2.40; 95% confidence interval: 0.69-8.37). CONCLUSIONS: It is important to identify the number of children who might benefit from neuropsychological assessment to inform prioritisation within existing resource and plan for additional resource if required. With a focus on reducing late effects, it is imperative that neuropsychological assessment is an integral component of a paediatric brain tumour programme.

Mitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor.

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP. LEARNING POINTS: Adrenocortical carcinoma is an important differential diagnosis for virilization in young childrenMitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosisMitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completedIn our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor.

The permanent defects in bone growth observed in preclinical studies of hedgehog (Hh) pathway inhibitors were not substantiated in early phase clinical studies of vismodegib in children. Consequently, vismodegib advanced into pediatric trials for malignancies suspected of being driven by aberrant activation of the Hh pathway. In one multicenter phase II trial, vismodegib was added to the therapy regimen for newly diagnosed Hh pathway activated medulloblastoma. Herein, we report on 3 children (2 on trial and one off trial) treated with vismodegib who developed widespread growth plate fusions that persist long after cessation of therapy. Currently, all 3 patients exhibit profound short stature and disproportionate growth, and 2 subsequently developed precocious puberty. Notably, the growth plate fusions only developed after a prolonged exposure to the drug (> 140 days). These findings resulted in a major trial amendment to restrict the agent to skeletally mature patients as well as a product label warning and update. Moreover, these findings alter the risk-benefit ratio of Hh inhibitors and underscore the importance of careful study of targeted agents in children.

Imatinib mesylate-induced pseudoporphyria in two children.

Imatinib mesylate was the first of several tyrosine kinase inhibitors approved for use in the treatment of a number of human cancers. Adverse cutaneous reactions to imatinib are common. Pseudoporphyria has been infrequently reported in adults undergoing imatinib therapy for chronic myeloid leukemia. We present two children with pseudoporphyria induced by imatinib therapy for hematologic malignancies. In view of the burgeoning use of imatinib in children, physicians should be aware that pseudoporphyria may develop as a consequence of imatinib therapy.

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.

Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.

Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial.

PURPOSE: To estimate the cumulative incidence of specific hormone deficiencies and the influence of hypothalamic-pituitary (HP) axis radiation dose in a cohort of children with embryonal brain tumors treated with risk-adapted craniospinal irradiation (CSI), conformal primary site irradiation, and high-dose chemotherapy. PATIENTS AND METHODS: Clinical data and HP axis radiation dosimetry data were obtained from 88 eligible children. All patients received regular endocrine follow-up that included screening tests of thyroid function and stimulation testing for growth hormone deficiency (GHD), and adrenocorticotropin hormone deficiency. RESULTS: The cumulative incidence of GHD, thyroid-stimulating hormone (TSH) deficiency, adrenocorticotropic hormone deficiency, and primary hypothyroidism at 4 years from diagnosis was 93% +/- 4%, 23% +/- 8%, 38% +/- 6%, and 65% +/- 7%, respectively. Radiation dosimetry to the HP axis was associated only with the development of TSH deficiency; the 4-year cumulative incidence was 44% +/- 19% and 11% +/- 8% (P = .014) for those receiving more or less than the median dose to the hypothalamus (>or= 42 v < 42 Gy), respectively. The median dose of CSI for the average-risk (AR) patients was 23.4 and 39.6 Gy (36 to 40.5 Gy) for the high-risk patients. The estimated mean decline in height Z-score after radiation therapy was greater in high-risk patients (-0.65 units/yr) when compared with AR patients (-0.54 units/yr; P = .039). CONCLUSION: Pediatric patients with CNS embryonal tumors are at high risk for treatment-related hormone deficiencies. GHD and primary hypothyroidism were diagnosed in a majority of subjects relatively soon after the completion of therapy. Radiation dose to the hypothalamus in excess of 42 Gy was associated with an increase in the risk of developing TSH deficiency.

Buccal swabs and treated cards: methodological considerations for molecular epidemiologic studies examining pediatric populations.

Self-collection of buccal cells provides a noninvasive method for obtaining biologic samples for genetic analyses in pediatric studies. Nevertheless, low yields, microbial contamination, and degradation of buccal samples present challenges for epidemiologic studies incorporating genetic investigations. The aims of this study were to compare the quality and yield of DNA extracted from buccal specimens with BuccalAmp swabs (Epicenter BioTechnologies, Madison, Wisconsin) or FTA cards (Whatman, Inc., Clifton, New Jersey) and to investigate the use of whole-genome amplification (WGA) for increasing DNA yields for single nucleotide polymorphism analyses. Buccal specimens were collected from 55 children with acute lymphoblastic leukemia and 52 control children without acute lymphoblastic leukemia in New South Wales, Australia, in 2003-2004. Real-time polymerase chain reaction was used to evaluate polymorphisms in the genes encoding the cytochrome p450 enzyme CYP3A4 (CYP3A4 A392G, also known as CYP3A4*1B) and the steroid xenobiotic receptor (SXR C25385T). Results showed that DNA could be isolated from buccal specimens collected by use of both methods and that yields could be substantially improved with WGA without introducing genotyping error. However, DNA quality was poorer in samples collected by BuccalAmp swabs, and the presence of polymerase chain reaction inhibitors in these samples reduced the sensitivity of quantitative real-time PCR analysis. These findings show that different methods for collecting buccal samples impact on the downstream success of genetic investigations and influence DNA quality after WGA.

Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia.

PURPOSE: Improved cure rates for children with acute lymphoblastic leukemia (ALL) have resulted from better relapse prediction, using clinical and laboratory features at diagnosis, and more intensive therapy in high-risk patients. More recently, measurements of the variation in the response of malignant lymphoblasts to chemotherapy in vivo have further improved relapse prediction. It is unknown whether the variation in the response of nonmalignant hematologic cells after chemotherapy correlates with the response of lymphoblasts or risk of relapse. PATIENTS AND METHODS: We retrospectively evaluated myelosuppression during induction and consolidation chemotherapy in 227 children uniformly treated for ALL on consecutive Australian and New Zealand Children's Cancer Study Group protocols. The early response to treatment was assessed in a representative subset (n = 62) by determining minimal residual disease (MRD) level by molecular techniques on the end-of-induction bone marrow sample. RESULTS: We found that a slow rate of myeloid recovery at the end of induction chemotherapy, reflected in a low absolute neutrophil count (ANC), was highly predictive of relapse (P < .0001). Additionally, patients with a high end-of-induction MRD level had a high risk of relapse (P = .001). Multivariate analysis confirmed the independent prognostic significance of MRD and ANC at the end of induction chemotherapy (P < .05). There was no significant association between other measures of myelotoxicity and MRD or relapse. CONCLUSION: We conclude that the responses of normal myeloid cells and malignant lymphoblasts to chemotherapy predict outcome by distinct mechanisms. While these results are promising, their use in the clinical setting needs to be examined in a future randomized controlled trial.