Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

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.

Chemotherapy-related cardiotoxicity: are Australian practitioners missing the point?

BACKGROUND: 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%. AIMS: To elucidate the incidence of anthracycline cardiotoxicity within a current paediatric oncology survivor cohort. METHODS: Participants were identified through the Haematology-Oncology database at the Royal Children's Hospital, Melbourne. Patients were identified from a retrospective audit of outpatient attendances between January 2008 and December 2015. Patients with a cancer diagnosis exposed to anthracyclines were eligible for the study. Patient demographics and echocardiogram findings were recorded with patients subcategorised according to degree of ACT. More significant ACT defined as fractional shortening (FS) <24% and less significant if FS 24-28% or a decline in baseline ejection fraction of >10%. RESULTS: Two hundred and eighty-six of a total 481 identified patients were eligible for study inclusion. Twenty patients displayed significant ACT with FS <24%. Ten patients had a FS 24-28% and 25 patients with a decline in ejection fraction from baseline of >10%. Overall, 6.6% demonstrated significant cardiac complications, whilst 19.6 % demonstrated some degree of ACT and decline in myocardial function. When stratified for cumulative anthracycline dose, the incidence of severe cardiac dysfunction was 5.1% (<250 mg/m2 ) and 25% (>250 mg/m2 ) CONCLUSION: This study demonstrates, in keeping with modern literature, the higher incidence of anthracycline associated cardiac toxicity and a need for better surveillance and follow up.

Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia.

BACKGROUND: Symptomatic neonatal hypoglycemia may be associated with later neurodevelopmental impairment. Brain injury patterns identified on early MRI scans and their relationships to the nature of the hypoglycemic insult and neurodevelopmental outcomes are poorly defined. METHODS: We studied 35 term infants with early brain MRI scans after symptomatic neonatal hypoglycemia (median glucose level: 1 mmol/L) without evidence of hypoxic-ischemic encephalopathy. Perinatal data were compared with equivalent data from 229 term, neurologically normal infants (control subjects), to identify risk factors for hypoglycemia. Neurodevelopmental outcomes were assessed at a minimum of 18 months. RESULTS: White matter abnormalities occurred in 94% of infants with hypoglycemia, being severe in 43%, with a predominantly posterior pattern in 29% of cases. Cortical abnormalities occurred in 51% of infants; 30% had white matter hemorrhage, 40% basal ganglia/thalamic lesions, and 11% an abnormal posterior limb of the internal capsule. Three infants had middle cerebral artery territory infarctions. Twenty-three infants (65%) demonstrated impairments at 18 months, which were related to the severity of white matter injury and involvement of the posterior limb of the internal capsule. Fourteen infants demonstrated growth restriction, 1 had macrosomia, and 2 had mothers with diabetes mellitus. Pregnancy-induced hypertension, a family history of seizures, emergency cesarean section, and the need for resuscitation were more common among case subjects than control subjects. CONCLUSIONS: Patterns of injury associated with symptomatic neonatal hypoglycemia were more varied than described previously. White matter injury was not confined to the posterior regions; hemorrhage, middle cerebral artery infarction, and basal ganglia/thalamic abnormalities were seen, and cortical involvement was common. Early MRI findings were more instructive than the severity or duration of hypoglycemia for predicting neurodevelopmental outcomes.