Anthony McCarthy

Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine.

AIMS To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODS Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94-->A and IVS2+21A-->C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTS Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A-->C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A-->C variants with thrombocytopenia (P = 0.012). CONCLUSIONS; Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

AIMS To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m(-2) day(-1)). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the models objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Fathers’ Views and Understanding of their Roles in Families with a Child with Acute Lymphoblastic Leukaemia An Interpretative Phenomenological Analysis

This study explored how fathers of children diagnosed with acute lymphoblastic leukaemia (ALL) perceived and understood the roles they had within their family over the course of their child’s illness and treatment. In-depth semi-structured interviews were conducted with five fathers. Transcripts were analysed using interpretative phenomenological analysis (IPA). The major themes that emerged were: adjusting to the diagnosis; the experience of maternal gate-keeping; striving for normalization; experiences of giving and receiving support. Overall, the fathers perceived themselves as having significant responsibility in helping their child and family cope with the illness experience. Clinical implications, including the need for professionals to recognize and more openly acknowledge the father’s position, are considered.

The development of an objective methodology to measure medication adherence to oral thiopurines in paediatric patients with acute lymphoblastic leukaemia-an exploratory study

AimsTo develop a method that prospectively assesses adherence rates in paediatric patients with acute lymphoblastic leukaemia (ALL) who are receiving the oral thiopurine treatment 6-mercaptopurine (6-MP).MethodsA total of 19 paediatric patients with ALL who were receiving 6-MP therapy were enrolled in this study. A new objective tool (hierarchical cluster analysis of drug metabolite concentrations) was explored as a novel approach to assess non-adherence to oral thiopurines, in combination with other objective measures (the pattern of variability in 6-thioguanine nucleotide erythrocyte concentrations and 6-thiouric acid plasma levels) and the subjective measure of self-reported adherence questionnaire.ResultsParents of five ALL patients (26.3%) reported at least one aspect of non-adherence, with the majority (80%) citing “carelessness at times about taking medication” as the primary reason for non-adherence followed by “forgetting to take the medication” (60%). Of these patients, three (15.8%) were considered non-adherent to medication according to the self-reported adherence questionnaire (scored ≥ 2). Four ALL patients (21.1%) had metabolite profiles indicative of non-adherence (persistently low levels of metabolites and/or metabolite levels clustered variably with time). Out of these four patients, two (50%) admitted non-adherence to therapy. Overall, when both methods were combined, five patients (26.3%) were considered non-adherent to medication, with higher age representing a risk factor for non-adherence (P < 0.05).ConclusionsThe present study explored various ways to assess adherence rates to thiopurine medication in ALL patients and highlighted the importance of combining both objective and subjective measures as a better way to assess adherence to oral thiopurines.

The need for preoperative α-adrenergic blockade for ganglioneuroma excision

ting position, arms rested on a table. When she reported fullness in her back and easing of pressure behind her eyes, further injection of blood in the epidural space was stopped. After the blood patch, she reported that her double vision resolved completely in standing position and she was discharged home without any complications. Abducens nerve, which has a long intracranial course, is often stretched with caudal sagging of brain structures due to intracranial hypotension. Prolonged stretching of abducent nerve can result in ischemia, palsy, and persistent diplopia despite correction of intracranial hypotension. Although adult literature reports that epidural blood patch consistently fails to relieve diplopia when performed more than 1 day after the onset of sixth cranial nerve palsy (2), we report an adolescent who developed diplopia for 3 days without positional headache following multiple lumbar punctures, having complete resolution of diplopia immediately after epidural blood patch. Clinicians need to be aware of atypical symptoms of intracranial hypotension such as positional diplopia in the absence of spinal headache following intentional (e.g. diagnostic lumbar punctures) or accidental (e.g. epidural catheter placement) dural punctures as these procedures are frequently carried out in children and adolescents. In children, lumbar epidural blood patches might be useful in relieving diplopia following intracranial hypotension due to CSF leak following dural punctures. Learning points

Congenital malignant peritoneal mesothelioma.

A. McCarthy Children’s Haematology Unit, Royal Belfast Hospital for Sick Children, Belfast, UK An 8-month-old boy presented with a 2-week history of dyspnoea, anorexia and increasing abdominal distension. Physical examination revealed a markedly distended abdomen, which was dull to percussion. US demonstrated a heterogeneous increase in hepatic echogenicity, with multiple intrahepatic cystic lesions (Fig. 1). There was extensive ascites. CT confirmed replacement of most of the right lobe of the liver by a multiloculated cystic lesion. The coeliac axis vessels and superior mesenteric artery were encased by the mass, as were the splenic, main and right portal veins and the IVC (Fig. 2). Aspiration of the liver cysts and peritoneal fluid gave chylous fluid, which contained clusters of ‘atypical’ cells and some reactive mesothelial cells. A liver biopsy was non-diagnostic, showing excess fibrosis and compressed hepatic parenchyma. Laparotomy demonstrated a retroperitoneal tumour that enveloped the IVC and invaded the liver via the portal vein. Subsequent histology revealed a diagnosis of congenital malignant peritoneal mesothelioma (MPM). The patient received palliative PICTORIAL INTERLUDE

Fifteen-minute consultation: Assessment, surveillance and management of hemihypertrophy

This article aims to provide a structured and concise guide for the general paediatrician managing a child with hemihypertrophy. Hemihypertrophy is a relatively uncommon condition. The significance is that a proportion of those affected are at risk of developing malignancies in childhood. For these children regular surveillance is required. We have outlined how one might assess and investigate a child presenting with hemihypertrophy. We have also formulated a practicable surveillance strategy which is in line with the current Royal College of Paediatrics and Child Health (RCPCH) guideline ‘Wilms’ tumour surveillance in at-risk children’.

The experience of fatherhood following childhood cancer survival

This study explored the experience of becoming a father following childhood cancer survival. Semi-structured interviews were conducted with five fathers and analysed using interpretative phenomenological analysis. Three superordinate themes emerged: ‘moving away from and revisiting the experience of cancer’, ‘making sense of fortune and loss following a life-threatening illness’ and ‘valuing the opportunity to be a father’. The transition to fatherhood brought unique and specific challenges to fathers. Nevertheless, all appeared to have positively adjusted to this transition. Findings recommended providing information and support to childhood survivors who wish to or who are about to become fathers.

Hickman line fracture in a road traffic accident

Sir, A 5-year-old oncology patient presented with a 24-h history of pain occurring whilst his Hickman line was being flushed. A linogram study was performed to check catheter integrity. It demonstrated a fracture involving both lumens of the right subclavian line (Fig. 1). A more detailed history was sought from the patient’s mother, who revealed they had been involved in a traffic accident the previous day, ironically, as they traveled in the back of an ambulance. The patient had been wearing a seat belt at the time and the shoulder strap had been over his right shoulder; the deceleration force of the accident had been translated directly to the catheter tubing.

A severe bleeding diathesis in a 6-year-old girl secondary to a composite diagnosis of splenic hemangiomatosis and small bowel lymphangiomatosis.

A 6-year-old girl presented with presumed relapse of childhood immune thrombocytopenia. Investigations revealed deranged coagulation parameters, abnormal small bowel thickening, and splenomegaly. A clinically significant bleeding diathesis emerged which was refractory to most hemostatic interventions. Laparatomy revealed a composite diagnosis of splenic hemangiomatosis and small bowel lymphangiomatosis. Splenectomy resulted in complete resolution of the coagulopathy. The diagnosis and management of these conditions is inherently complex and without clear guidance. We discuss our perioperative management of the bleeding diathesis. There is a need for long-term follow-up of the underlying pathologies particularly as potentially useful therapeutic agents have emerged.