The Australian New Zealand Consortium in Children, Adolescents, and Young Adults Oncofertility action plan.

International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).

Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study.

DNA methylation array profiling for classifying pediatric central nervous system (CNS) tumors is a valuable adjunct to histopathology. However, unbiased prospective and interlaboratory validation studies have been lacking. The AIM BRAIN diagnostic trial involving 11 pediatric cancer centers in Australia and New Zealand was designed to test the feasibility of routine clinical testing and ran in parallel with the Molecular Neuropathology 2.0 (MNP2.0) study at Deutsches Krebsforschungszentrum (German Cancer Research Center). CNS tumors from 269 pediatric patients were prospectively tested on Illumina EPIC arrays, including 104 cases co-enrolled on MNP2.0. Using MNP classifier versions 11b4 and 12.5, we report classifications with a probability score ≥0.90 in 176 of 265 (66.4%) and 213 of 269 (79.2%) cases, respectively. Significant diagnostic information was obtained in 130 of 176 (74%) for 11b4, and 12 of 174 (7%) classifications were discordant with histopathology. Cases prospectively co-enrolled on MNP2.0 gave concordant classifications (99%) and score thresholds (93%), demonstrating excellent test reproducibility and sensitivity. Overall, DNA methylation profiling is a robust single workflow technique with an acceptable diagnostic yield that is considerably enhanced by the extensive subgroup and copy number profile information generated by the platform. The platform has excellent test reproducibility and sensitivity and contributes significantly to CNS tumor diagnosis.

LIN28 expression and function in medulloblastoma.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatment modalities are not completely effective and can lead to severe neurological and cognitive adverse effects. In addition to urgently needing better treatment approaches, new diagnostic and prognostic biomarkers are required to improve the therapy outcomes of MB patients. The RNA-binding proteins, LIN28A and LIN28B, are known to regulate invasive phenotypes in many different cancer types. However, the expression and function of these proteins in MB had not been studied to date. This study identified the expression of LIN28A and LIN28B in MB patient samples and cell lines and assessed the effect of LIN28 inhibition on MB cell growth, metabolism and stemness. LIN28B expression was significantly upregulated in MB tissues compared to normal brain tissues. This upregulation, which was not observed in other brain tumors, was specific for the aggressive MB subgroups and correlated with patient survival and metastasis rates. Functionally, pharmacological inhibition of LIN28 activity concentration-dependently reduced LIN28B expression, as well as the growth of D283 MB cells. While LIN28 inhibition did not affect the levels of intracellular ATP, it reduced the expression of the stemness marker CD133 in D283 cells and the sphere formation of CHLA-01R cells. LIN28B, which is highly expressed in the human cerebellum during the first few months after birth, subsequently decreased with age. The results of this study highlight the potential of LIN28B as a diagnostic and prognostic marker for MB and open the possibility to utilize LIN28 as a pharmacological target to suppress MB cell growth and stemness.

Osteosarcoma in a Child Below 2 Years of Age: Case Report and Review of the Literature.

BACKGROUND: Osteosarcoma in children below the age of 5 is extremely rare. OBSERVATION: We report on a previously well 14-month-old male infant, who presented with a reluctance to weight-bear on his right leg and had an associated limp. Plain imaging and a magnetic resonance imaging scan demonstrated a lytic lesion in the right distal femur. An open surgical biopsy confirmed the diagnosis of osteosarcoma. There was no significant family history of cancer and genetic screening for Li-Fraumeni syndrome was negative. CONCLUSIONS: This case highlights the importance of timely consideration of osteosarcoma in an infant, when the clinical presentation and medical imaging are consistent with that diagnosis.

Favourable outcomes for childhood acute lymphoblastic leukaemia in an isolated setting: The Tasmanian experience.

BACKGROUND: Tasmania is a large, relatively isolated island located south of mainland Australia with limited tertiary level paediatric oncology services. AIMS: To benchmark regional outcomes for childhood acute lymphoblastic leukaemia (ALL) against published international standards. METHODS: We undertook a retrospective cohort study, analysing the clinical characteristics and health outcomes of all children diagnosed with and treated for ALL in Tasmania, Australia between 2006 and 2015. RESULTS: Thirty-five patients aged less than 18 years were diagnosed with ALL in the study's 10-year period. Twenty-eight cases were precursor B cell in origin, with 7 cases of T-cell ALL. The great majority of children (30/35; 86%) received their entire first line treatment in Tasmania. Major treatment-related toxicities, including allergic drug reactions, and episodes of acute pancreatitis, deep venous thrombosis and bacterial sepsis, were managed locally, with one death secondary to overwhelming infection and multiorgan failure. The overall and event-free survival rates for childhood ALL were 30/35 (86%) and 28/35 (80%), respectively. CONCLUSIONS: These results compare favourably with published results from large international cooperative group trials based in developed countries. Continued local treatment with appropriate support from a dedicated specialist paediatric oncology unit is therefore justified.

Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy.

Pediatric low-grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small Phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single-institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multiagent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560 mg/m(2), four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% CI 57-76%), and 5-year PFS was 51% (95% CI 41-63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG.

Pulmonary Function After Treatment for Embryonal Brain Tumors on SJMB03 That Included Craniospinal Irradiation.

PURPOSE: The treatment of children with embryonal brain tumors (EBT) includes craniospinal irradiation (CSI). There are limited data regarding the effect of CSI on pulmonary function. METHODS: Protocol SJMB03 enrolled patients 3 to 21 years of age with EBT. Pulmonary function tests (PFTs) (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC] by spirometry, total lung capacity [TLC] by nitrogen washout or plethysmography, and diffusing capacity of the lung for carbon monoxide corrected for hemoglobin [DLCO(corr)]) were obtained. Differences between PFTs obtained immediately after the completion of CSI and 24 or 60 months after the completion of treatment (ACT) were compared using exact Wilcoxon signed-rank tests and repeated-measures models. RESULTS: Between June 24, 2003, and March 1, 2010, 303 eligible patients (spine dose: ≤ 2345 cGy, 201; >2345 cGy, 102; proton beam, 20) were enrolled, 260 of whom had at least 1 PFT. The median age at diagnosis was 8.9 years (range, 3.1-20.4 years). The median thoracic spinal radiation dose was 23.4 Gy (interquartile range [IQR], 23.4-36.0 Gy). The median cyclophosphamide dose was 16.0 g/m(2) (IQR, 15.7-16.0 g/m(2)). At 24 and 60 months ACT, DLCO(corr) was <75% predicted in 23% (27/118) and 25% (21/84) of patients, FEV1 was <80% predicted in 20% (34/170) and 29% (32/109) of patients, FVC was <80% predicted in 27% (46/172) and 28% (30/108) of patients, and TLC was <75% predicted in 9% (13/138) and 11% (10/92) of patients. DLCO(corr) was significantly decreased 24 months ACT (median difference [MD] in % predicted, 3.00%; P = .028) and 60 months ACT (MD in % predicted, 6.00%; P = .033) compared with the end of radiation therapy. These significant decreases in DLCO(corr) were also observed in repeated-measures models (P = .011 and P = .032 at 24 and 60 months ACT, respectively). CONCLUSIONS: A significant minority of EBT survivors experience PFT deficits after CSI. Continued monitoring of this cohort is planned.

Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma.

BACKGROUND: Management of low-grade gliomas (LGG) can be a challenge, particularly when not resectable and refractory or recurrent following standard treatments. We undertook a retrospective analysis of 2 institutions' experiences treating children for refractory or progressive LGG with bevacizumab-based therapy (BBT). PROCEDURE: Inclusion criteria were patients younger than 18 years of age who had previously failed one or more lines of therapy. Treatment was intravenous bevacizumab 10 mg/kg and intravenous irinotecan 125 to 150 mg/m2 every 2 weeks. RESULTS: Sixteen children (median age of 8.6 y), 5 with neurofibromatosis type 1 and 8 with disseminated disease were treated between 2009 and 2013. Median duration of treatment was 12 months (range, 3 to 45 mo). Seven patients (44%) showed clinical improvement (3 patients within a month) and 8 patients (50%) remained clinically stable during BBT. Imaging studies showed 3 (19%) had a partial response, 11 (69%) stable disease, and 2 (12%) had progressive disease. Four patients had progressive disease after stopping BBT (median duration of 5 mo). Three of these 4 were able to be retreated with BBT and all achieved an objective response. Treatment was well tolerated with no grade 3 or 4 toxicities related to bevacizumab. Irinotecan was discontinued in 4 patients because of grade 2-3 toxicities. CONCLUSIONS: We conclude that BBT is well tolerated and led to disease control in patients with refractory or recurrent cases of LGG. Retreatment with BBT led to disease control in most of these cases. Larger, prospective studies are warranted to confirm these results.

Childhood cancers in families with and without Lynch syndrome.

Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24%) and non-Lynch syndrome families (179/94,302; 0.19%; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95% CI 107-206) per million population per year in Lynch syndrome families and 115 (95% CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families.

Vehicle refuelling, use of domestic wood heaters and the risk of childhood brain tumours: Results from an Australian case-control study.

BACKGROUND: The aetiology of childhood brain tumours (CBT) is largely unknown. Damage to germ cells after parental exposure to airborne carcinogens, such as volatile organic compounds and polycyclic aromatic hydrocarbons is one plausible pathway. This analysis aimed to investigate whether parental refuelling of vehicles or the use of domestic wood heaters in key time periods relating to the child's birth was associated with an increased risk of CBT. PROCEDURE: Cases <15 years of age were recruited through 10 paediatric oncology centres around Australia; controls were recruited through nationwide random-digit dialling, frequency matched to cases on age, sex and State of residence. Exposure to refuelling and wood heaters was ascertained through questionnaires from both parents. Odds ratios (ORs) and confidence intervals (CIs) were estimated using unconditional logistic regression, adjusting for relevant covariates. RESULTS: Data were available for 306 case and 950 control families. Paternal refuelling ≥4 times/month was associated with an increased risk of CBT (OR 1.59, 95% CI: 1.11, 2.29), and a dose-dependent trend was observed (P = 0.004). No association was seen for maternal refuelling. Use of closed, but not open, wood heaters before (OR 1.51, 95% CI: 1.05, 2.15) and after (OR 1.44, 95% CI: 1.03, 2.01) the child's birth was associated with increased risk of CBT, but dose-response relationships were weak or absent. CONCLUSIONS: Paternal refuelling of vehicles ≥4 times/month and the use of closed wood heaters before the child's birth may increase the risk of CBT. Replication in larger studies is needed. Pediatr Blood Cancer 2015;62:229-234. © 2014 Wiley Periodicals, Inc.

Cancer risks for relatives of children with cancer.

We determined the extent and distribution of cancers in relatives of 379 children newly diagnosed with cancer. Family history was collected from 1,337 first-degree and 3,399 second-degree relatives and incidence compared with national age- and gender-specific rates. Overall, 14 children (3.7%) had a relative with a history of childhood cancer and 26 children (6.9%) had a first-degree relative with a history of cancer, with only one of these having an identifiable familial cancer syndrome. There was a higher than expected incidence of childhood cancer among first-degree relatives (parents and siblings) (standardized incidence ratio (SIR) 1.43; 95% CI 0.54-5.08). There was also a higher than expected incidence of adult cancers among first-degree relatives (SIR 1.45; 95% CI 0.93-2.21), particularly in females (SIR 1.82; 95% CI 1.26-3.39). The increased family cancer history in first-degree females was largely attributable to an effect in mothers (SIR 1.78; 95% CI 1.27-3.33). The gender-specific association was reflected in higher than expected incidence rates of breast cancer in both mothers (SIR 1.92; 95% CI 0.72-6.83) and aunts (SIR 1.64; 95% CI 0.98-2.94). These findings support the hypothesis that previously undetected familial cancer syndromes contribute to childhood cancer.

Concordance between the chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma.

BACKGROUND: Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed. PROCEDURES: Audiological evaluations were reviewed for 379 patients with newly diagnosed medulloblastoma (ages 3-21 years). Each patient was enrolled on one of two St. Jude clinical protocols that included craniospinal radiation therapy and four courses of 75 mg/m(2) cisplatin chemotherapy. The latest audiogram conducted 5.5-24.5 months post-protocol treatment initiation was graded using the Chang and SIOP ototoxicity criteria. Clinically significant hearing loss was defined as Chang grade ≥2a and SIOP ≥2. Hearing loss was considered serious (requiring a hearing aid) at the level of Chang grade ≥2b and SIOP ≥3. RESULTS: A strong concordance was observed between the Chang and SIOP ototoxicity scales (Stuart's tau-c statistic = 0.89, 95% CI: 0.86, 0.91). Among those patients diagnosed with serious hearing loss, the two scales were in good agreement. However, the scales deviated from one another in classifying patients with less serious or no hearing loss. CONCLUSIONS: Although discrepancies between the Chang and SIOP ototoxicity scales exist primarily for patients with no or minimal hearing loss, the scales share a strong concordance overall.

Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma.

BACKGROUND: The purpose of this study was to evaluate amifostine for protection from cisplatin-induced serious hearing loss in patients with average-risk medulloblastoma by extending a previous analysis to a much larger sample size. In addition, this study aimed to assess amifostine with serious hearing loss in patients with high-risk medulloblastoma treated with cisplatin. METHODS: Newly diagnosed medulloblastoma patients (n = 379; ages 3-21 years), enrolled on one of 2 sequential St. Jude clinical protocols that included 4 courses of 75 mg/m(2) cisplatin, were compared for hearing loss by whether or not they received 600 mg/m(2) of amifostine immediately before and 3 hours into each cisplatin infusion. Amifostine administration was not randomized. The last audiological evaluation between 5.5 and 24.5 months following protocol treatment initiation was graded using the Chang Ototoxicity Scale. A grade of ≥ 2b (loss requiring a hearing aid or deafness) was considered a serious event. RESULTS: Among average-risk patients (n = 263), amifostine was associated with protection from serious hearing loss (adjusted OR, 0.30; 95% CI, 0.14-0.64). For high-risk patients (n = 116), however, there was not sufficient evidence to conclude that amifostine prevented serious hearing loss (OR, 0.89; 95% CI, 0.31-2.54). CONCLUSIONS: Although patients in this study were not randomly assigned to amifostine treatment, we found evidence in favor of amifostine administration for protection against cisplatin-induced serious hearing loss in average-risk but not in high-risk, medulloblastoma patients.

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.

Parental alcohol consumption and risk of childhood acute lymphoblastic leukemia and brain tumors.

PURPOSE: Childhood acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and brain tumors (CBTs) are the leading cause of cancer death in children. In our Australian case-control studies of these cancers, we investigated whether parental alcohol consumption before or during pregnancy was associated with risk. METHODS: Cases were identified through the ten Australian pediatric oncology centers, and controls were recruited through national random-digit dialling. Detailed information on alcohol consumption, including beverage type, amount, and timing, was collected from 690 case families (388 ALL and 302 CBT) and 1,396 control families. Data were analyzed using unconditional logistic regression. RESULTS: We found no evidence that maternal alcohol use before or during pregnancy was associated with an increased risk of either cancer; rather, there was evidence of inverse associations, particularly with wine. For both cancers, we observed U-shaped associations with paternal alcohol consumption in the year before the pregnancy, possibly driven by reduced risk at moderate levels of beer and wine intake and increased risk associated with high levels of beer intake. Moderate intake of spirits by fathers was associated with an increased risk of CBT but not ALL. These findings would be strengthened by corroboration in other studies. While the inverse associations with wine may be interesting mechanistically, the public health message remains that maternal alcohol use during pregnancy causes serious disorders in the offspring and should be avoided. CONCLUSIONS: Our findings suggest that men, as well as women, should limit their alcohol intake when planning a pregnancy.