Dermot Murphy

Place of death and hospital care for children who died of cancer in England, 1999-2006.

AIM To describe patterns of hospital care and to evaluate factors influencing place of death for children who died after a diagnosis of cancer in England during 1999-2006. MATERIALS AND METHODS Registrations of children on the National Registry of Childhood Tumours (NRCT) who were diagnosed with cancer and died during 1999-2006 in England were linked to the Hospital Episode Statistics (HES) and to death certificates. Multivariable logistic modelling was used to assess factors that influence dying at home or in hospital. RESULTS 1864 (96%) of children with cancer registrations were linked to HES records. The validation of hospital as a place of death and ethnicity between data sources was good, although anomalies within HES data exist. Similar proportions of children are dying at home (45%) and in hospital (47%), and the percentage dying in a hospice or care home increased from 2% to 10%. Of the children who died in hospital, 74% were admitted as emergencies or as a transfer from another hospital. Greater proportions of children were diagnosed with a leukaemia or lymphoma, those dying within six months of diagnosis, Asian and Black children, those from a deprived background and those not treated in a CCLG centre died in a hospital. CONCLUSIONS Patterns of hospital care varied considerably by type of cancer, death within six months of diagnosis, ethnicity and deprivation. Further research is required to elucidate explanations for these patterns and to evaluate methods to increase the proportion of children dying at home who wish to do so.

Childhood phaeochromocytoma and paraganglioma: 100% incidence of genetic mutations and 100% survival

INTRODUCTION The aim is to identify the incidence of genetic mutations and outcome of children presenting with phaeochromocytoma/paraganglioma (PGL) to a single paediatric surgical service to determine the need for genetic counselling in associated kindreds. METHODS A retrospective case note review was undertaken of all cases treated between 1998 and 2008 with particular reference to presentation, management, and predisposing genetic conditions. RESULTS Seven cases (4 male, 3 female) were identified (median age, 13 years; interquartile range, 9-16). Three cases had a family history of phaeochromocytoma/PGL. All presented with neurologic symptoms related to hypertension, including headaches (n = 5), hemiparesis (n = 2), facial palsy, and hemianopia. All underwent surgical resection. Five patients had meta-iodobenzylguanidine (MIBG) therapy for apparently malignant features. All cases were found to have a predisposing genetic mutation: von Hippel-Lindau (n = 3), succinate dehydrogenase mutations (n = 3), and multiple endocrine neoplasia (n = 1). All patients are alive after a median follow-up of 5 (interquartile range, 2-7) years. CONCLUSIONS All 7 cases had a familial genetic mutation identified, and none arose de novo. We advocate genetic counselling for all families of children diagnosed with phaeochromocytoma/PGL with lifelong surveillance tailored to the underlying syndrome because of the increased risk of synchronous and metachronous tumours associated with these genetic syndromes.

Vincristine sulfate as a possible cause of optic neuropathy

A 6‐year‐old boy with skin lesions suggestive of neurofibromatosis developed a frontotemporal primitive neuroectodermal tumor and was subsequently treated with surgery, craniospinal irradiation, and chemotherapy. After the sixth cycle of treatment with vincristine sulfate, 9 months after diagnosis, the child developed a rapidly progressive bilateral deterioration in visual acuity. Retinal appearances were consistent with optic neuropathy. Gene studies for neurocutaneous syndromes were negative. Brain imaging at this time showed no tumor progression, and in the absence of other etiologies, we implicate vincristine as a probable cause. Discontinuation of this particular agent has allowed bilateral improvement in visual acuity. Pediatr Blood Cancer 2007;48:238–240.

Carboplatin therapeutic monitoring in preterm and full-term neonates

Introduction Administration of the most appropriate dose of chemotherapy to neonates is particularly challenging and frequently not standardised based on any scientific rationale. We report the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life. Methods Carboplatin therapeutic monitoring was performed to achieve target drug exposures area under the plasma concentration–time curve (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma treated over an 8 year period. Carboplatin was administered over 3 days with therapeutic drug monitoring utilised to target cumulative AUC values of 5.2–7.8 mg/ml min. Results AUC values achieved were within 15% of target values for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on initial mg/kg dosing schedules. Carboplatin clearance determined across three consecutive chemotherapy courses in two patients increased from 3.4 to 7.1 ml/min and from 7.2 to 16.5 ml/min, representing increases of 210–230% over several weeks of treatment. Complete remission was observed in 8/9 patients, with no renal toxicity reported and only one patient experiencing ototoxicity. Conclusion The study highlights the benefits of utilising therapeutic drug monitoring to achieve target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of marked increases in drug clearance observed over consecutive chemotherapy courses. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform future treatment.

Age-related medical decision limits for urinary free (unconjugated) metadrenalines, catecholamines and metabolites in random urine specimens from children.

Background Neuroblastoma is the most common extracranial solid tumour in childhood (8% of all childhood cancers), the most frequently diagnosed in infancy, and has one of the highest death rates, while chromaffin tumours rarely present in childhood. Both tumour types produce catecholamines and their metabolites. It is difficult to produce reference ranges for tests in children, and currently, no age-related medical decision limits for free metadrenalines (free metanephrines) in random urine specimens exist in the paediatric literature. Methods Results of vanillylmandelic acid (VMA), 5-hydroxyindoleacetic acid, homovanillic acid (HVA), noradrenaline (NA), adrenaline, dopamine (DA), free normetadrenaline (fNMA), free metadrenaline and free 3-methoxytyramine (f3MT) in 1658 random urines obtained from infants, children and young adults were measured by high performance liquid chromatography with electrochemical detection. Specimens were excluded from consideration if obtained from the following categories, i.e. (a) harbouring neuroblastic, chromaffin, carcinoid or other tumours or malignancies; (b) medical conditions having known association with excess catecholamine excretion; (c) patients administered catecholamine or paracetamol; (d) overly dilute urine; and (e) manifesting outlying values following visual inspection. Results There remained 872 specimens that were grouped into seven age ranges (<1; 1 or 2; 3 or 4; 5–7; 8–10; 11–13; 14–19 y) for which medical decision limits were determined for each analyte. There was no significant difference between the results for boys or girls. In 55 patients harbouring neuroblastic tumours, HVA (54/55), f3MT (14/16), VMA (45/53) and DA (43/53) were the most frequently elevated analytes at time of diagnosis. In 11 patients presenting in childhood with chromaffin tumours, fNMA (11/11) followed by NA (10/11) were the most frequently elevated. Discussion The likely reasons for outlying or missing values, together with the reasons for variation in the distinctive biochemical patterns of analytes exhibited in individuals harbouring either neuroblastic or chromaffin tumours are discussed.

Langerhans cell histiocytosis: 23 years' paediatric experience highlights severe long-term sequelae.

Purpose To review the presentation and outcome of patients with Langerhans cell histiocytosis attending The Royal Hospital for Sick Children, Glasgow over a 23-year period. Method Thirty-one children were diagnosed with Langerhans cell histiocytosis between January 1990 and December 2012. Retrospective information from medical records was gathered on age at diagnosis, presenting symptoms, classification of disease, treatment and long-term outcome. Results There were 17 boys and 14 girls; median age at diagnosis 2 years 9 months (interquartile range: 1 year 6 months to 4 years 4 months). Eleven were below 2 years and two were below 6 months of age at diagnosis. Eighteen (58%) children had single system disease of which four were multifocal; 13 (42%) had multisystem disease. Seventeen children improved with conservative treatment. Fourteen required steroids and dual agent chemotherapy; three required further chemotherapy. One child died. Two children had successfully treated relapses. Ten developed diabetes insipidus, seven were growth hormone deficient, two suffered from hypothyroidism and one panhypopituitarism. Median follow-up of the cohort was 8 years 10 months (interquartile range: 5 years 5 months to 12 years 7 months). Conclusion Langerhans cell histiocytosis is a rare disease in infants and young children, with a variable course ranging from self-limiting to life threatening. In very young children (under 2 years of age), multisystem disease is more common, requiring intensive chemotherapy and lifelong follow-up. Lasting sequelae were identified in over a third of patients, including endocrine dysfunction, hearing difficulties, neurological and psychological problems.

Leukocoria and retinoblastoma—pitfalls of the digital age?

Retinoblastoma is a childhood cancer that is now highly curable. Parents may be alerted to the disease when photographs of their child reveal a white pupil (leukocoria). In our case of a 15-month-old girl, one of her parents was a keen photographer and immediately noticed pupilliary abnormalities on digital photography (fi gure A). Application of red-eye reduction software improved the abnormal right pupil but the diseased left pupil remained white (fi gure B). Although the abnormal white refl ection from the retina was detected in this case, it is of note that the parent was easily able to

Predicting, Monitoring, and Managing Hypercalcemia Secondary to 13-Cis-Retinoic Acid Therapy in Children With High-risk Neuroblastoma.

13-cis-retinoic acid is an established component of treatment for children with high-risk neuroblastoma. However, significant hypercalcemia is increasingly recognized as a potentially life-threatening dosage-related side effect. We present 2 patients with significant hypercalcemia secondary to 13-cis-retinoic acid and their management, and identified the predictive factors for susceptibility to hypercalcemia. Assessing glomerular filtration rate and concomitant medication help predict individual susceptibility to hypercalcemia. Calcium levels should be monitored at days 1, 7, and 14 of each course of retinoic acid. An algorithm for the management of hypercalcemia during the affected and subsequent cycles of retinoid therapy is proposed.

Chemotherapy and Novel Cancer Targeted Therapies

Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70 %. Although improvements in radiotherapy and surgery have reduced the late sequelae of curative therapy, chemotherapy still remains the mainstay of treatment for most childhood cancers. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of late effects can be considerable. The current paradigm for new cancer therapies is to increase our knowledge of the molecular basis of carcinogenesis, followed by the development of cancer-cell specific therapies. During the past 10 years, initiatives have been undertaken by paediatric oncologists to further promote the clinical evaluation of new anti cancer compounds in children within national academic paediatric groups. Through proper evaluation in collaborative clinical trials we will learn how best to use these new therapeutic approaches and improve the survival rates and reduce toxicity for children with cancer.

Paediatric Palliative Care

Death, much like sex, is a topic that adults find hard to discuss among themselves let alone with their children). The conversation may be painful for both parties and there is a natural desire to protect children from harm. This ignores the fact that death is an integral part of childhood and that a failure to have an open conversation about childhood mortality can lead to significant misunderstandings at both an individual and societal levels.