Male and female experiences of having fertility matters raised alongside a cancer diagnosis during the teenage and young adult years.

Discussion and management of potential reproductive health sequelae of adolescent cancer are essential and challenging components of care for the multidisciplinary team. Despite this, research has been limited to specific experiences (e.g. sperm banking) or fertility-related concerns of adult survivors. This grounded theory study of 38 male and female survivors of adolescent cancer aged 16-30 years drew on in-depth single interviews to map the range of experiences of being advised that treatment might affect fertility. Strong support for being told at around diagnosis was found regardless of gender, age, incapacity or availability of fertility preservation services. Age and life stage appeared less significant for impact than the perceived level of threat to personal and social well-being. Women were more likely to achieve lower levels of comprehension about the physiological impact, to report later distress from lack of fertility preservation services and to revisit more frequently those decisions made by the few offered fertility preservation. Men found decision making about sperm banking straightforward on the whole and reported satisfaction with having the choice regardless of outcome. Findings suggest that young people can cope with this information alongside diagnosis especially when professional and parental support is proportionate to the particular impact on them.

Malignant germ cell tumours of childhood: new associations of genomic imbalance.

Malignant germ cell tumours (MGCTs) of childhood are a rare group of neoplasms that comprise many histological subtypes and arise at numerous different sites. Genomic imbalances have been described in these tumours but, largely because of the paucity of cases reported in the literature, it is unclear how they relate to abnormalities in adult MGCTs and impact on potential systems for classifying GCTs. We have used metaphase-based comparative genomic hybridisation to analyse the largest series of paediatric MGCTs reported to date, representing 34 primary tumours (22 yolk sac tumours (YSTs), 11 germinomatous tumours and one metastatic embryonal carcinoma) occurring in children from birth to age 16, including 17 ovarian MGCTs. The large dataset enabled us to undertake statistical analysis, with the aim of identifying associations worthy of further investigation between patterns of genomic imbalance and clinicopathological parameters. The YSTs showed an increased frequency of 1p- (P=0.003), 3p+ (P=0.02), 4q- (P=0.07) and 6q- (P=0.004) compared to germinomatous tumours. Gain of 12p, which is invariably seen in adult MGCTs, was present in 53% of primary MGCTs of children aged 5-16 and was also observed in four of 14 YSTs affecting children less than 5. Two of these cases (14% of MGCTs in children less than 5) showed gain of the 12p11 locus considered to be particularly relevant in adult MGCTs. Gain of 12p showed a significant association with gain of 12q. Conversely, MGCTs without 12p gain displayed a significantly increased frequency of loss on 16p (P=0.04), suggesting that this imbalance may contribute to tumour development in such cases. This data provides new insight into the biology of this under-investigated tumour group and will direct future studies on the significance of specific genetic abnormalities.

Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment.

Hepatic veno-occlusive disease (HVOD) following bone marrow transplantation is potentially fatal. Criteria for diagnosis and starting treatment are mainly based on adult studies. Recombinant tissue plasminogen activator (rtPA) has been used with variable success. rtPA and heparin were given to 12 children (nine with immunodeficiency, two malignancy, one thalassaemia) with moderate to severe HVOD. Of the 12, 10 responded with a fall in bilirubin concentration; eight survived with complete resolution of HVOD. Four of the five patients with associated multiorgan failure (MOF) died despite rtPA treatment. One child suffered significant, and one minor, bleeding during rtPA treatment. A scoring system for quantifying the severity of HVOD in children is proposed, incorporating the criteria used to diagnose HVOD, risk factors for its development and also parameters reflective of the patient's general condition. This will facilitate early diagnosis and management of those cases which, if not treated promptly, are likely to deteriorate with an adverse outcome. Our experience suggests rtPA and heparin are an effective treatment for HVOD in children, with relatively little toxicity provided therapy is started before MOF develops.

Costs and consequences of different chemotherapy regimens in metastatic colorectal cancer.

An economic sub-study was run alongside a large multi-centre randomised trial (MRC-CR06) comparing three chemotherapy regimens; de Gramont, Lokich and raltitrexed in patients with metastatic colorectal cancer. Patients in six of 45 centres in the main trial were approached to take part in the sub-study. Chemotherapy delivery costs were assessed in each sub-study centre with external validity verified by questionnaire to all other centres. Patient representativeness was assessed. Stochastic resource use data, including patient borne costs and non-hospital health service resource use were monitored prospectively. Mean total societal costs were de Gramont= 5051 pounds sterling (s.d. 1910 pounds sterling ), raltitrexed= 2616 pounds sterling (s.d. 991 pounds sterling ) and Lokich= 2576 pounds sterling (s.d. 1711 pounds sterling ). In pairwise comparisons, statistically significant mean total cost differences were shown for de Gramont vs Lokich (mean difference= 2475 pounds sterling , 95%CI 914 pounds sterling - 4037 pounds sterling , P<0.01) and for de Gramont vs raltitrexed (mean difference= 2435 pounds sterling, 95%CI 922 pounds sterling - 2948 pounds sterling , P<0.01). Sensitivity analyses showed little effect on overall costs. The main trial showed de Gramont and Lokich to be equally effective in terms of survival, quality of life and response rates but Lokich had higher toxicity and hand-foot syndrome. Raltitrexed showed similar response rates and overall survival but increased toxicity and inferior quality of life making it a clinically inferior regimen despite its ease of administration and costs. For a comparable clinical outcome, Lokich can be administered for approximately half the cost of de Gramont.

A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin.

Pre-clinical studies indicate that cisplatin encapsulated in STEALTH((R))liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m(-2)by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.

Wilm's tumour presenting as acute sexual assault.

A 3-year-old presented with severe apparent perineal bleeding. The parents description of a precipitating accident did not provide an adequate explanation for the bleeding. Examination under anaesthesia with police presence revealed no genital injury. Palpation of the abdomen revealed a large renal mass. It was found that the child had a Stage 4 Wilm's Tumour.

Plasma coenzyme Q(10) in children and adolescents undergoing doxorubicin therapy.

The objective of this study was to test the hypothesis that doxorubicin treatment for cancer in childhood and adolescence causes a dose-related decrease in the concentration of plasma coenzyme Q(10). The concentration of plasma coenzyme Q(10) was measured before and after administration of doxorubicin in six patients, and before and after chemotherapy in six patients undergoing treatments that did not include doxorubicin. There was a significant increase in the concentration of plasma coenzyme Q(10) in post-treatment samples compared to pre-treatment samples in patients treated with doxorubicin (P=0.008; n=32), whereas there were no significant changes in plasma coenzyme Q(10) concentrations in patients treated with chemotherapy that did not include doxorubicin. (P=0.770; n=30). We hypothesise that the increase in plasma coenzyme Q(10) that was observed in patients undergoing doxorubicin treatment is due to release of coenzyme Q(10) from apoptotic or necrotic cardiac tissue. We conclude that the cardiotoxicity due to doxorubicin therapy does not involve acute myocardial depletion of coenzyme Q(10).

Multi-disciplinary research can be more than parallel-disciplinary research: the case of GPs' use of magnetic resonance imaging.

OBJECTIVES: We aimed to show how in multi-disciplinary research data collected to meet the needs of one discipline can provide information of value to another. METHODS: Using the critical incident technique, 25 GPs were interviewed about recent scans requested for patients with knee and lumbar spine complaints. Transcripts of the interviews were scrutinized from both a medical and an economic perspective. RESULTS: Five key economic issues where further research is needed were identified. CONCLUSIONS: The total value of the information provided by multi-disciplinary research may exceed the sum of the information collected to meet the requirements of the individual disciplines.

Progressive glomerular toxicity of ifosfamide in children.

Glomerular toxicity following ifosfamide (IFO) is not as well recognized as renal tubular damage. Following a case of ifosfamide-induced renal failure with histological evidence of glomerular changes, we undertook a retrospective study of all IFO-treated children to assess the extent and severity of its glomerular toxicity and to identify possible predisposing factors. Thirty-seven children with a follow-up of 6 months or more from the end of chemotherapy were studied. They were a median of 10.8 years old (range 3.25-18.5), had received a median of 54 g/m2 (range 9-135) of IFO, and had a median follow-up of 29 months (range 6-68). The criteria to identify glomerular dysfunction were raised plasma creatinine (Pc) values on two occasions or a low glomerular filtration rate (GFR) measured by Tc-99-DTPA clearance. Detailed assessment was carried out to identify other nephrotoxic influences in these children. Subjects in whom glomerular dysfunction could be causally linked to IFO were compared with the rest of the group for a variety of predisposing factors. Of eight children with glomerular dysfunction, two had other nephrotoxic influences and were excluded from further analysis. In six (17.1%) children, glomerular dysfunction appeared to be causally linked to IFO. Their median GFR was 61.9 ml/min/1.73 m2(range 33-85) and Pc was 123 mumol/l (range 85-216). Five of the six had normal glomerular function at the end of therapy and the raised Pc values were first noted 19, 21, 26, 29, and 36 months later. Children with glomerular toxicity had a significantly longer median follow-up (41.5 vs. 19 months; P = 0.04) than the rest of the group, suggesting late onset of this problem. They were older at the time of the study and had received nearly twice the dose of IFO, though the differences in age and dose did not reach statistical significance. The earliest signs of renal toxicity were seen in the index case, who had had prior nephrectomy. All affected children had coexistent and preceding tubular toxicity. The inadequacies of tests commonly used to assess glomerular function and the possibility of underestimation of dysfunction are discussed. Glomerular dysfunction following IFO is poorly recognized and evidence from this study of its later onset and progressive nature is a cause for concern. The index case is described with histological findings.

Red blood cell hypoxanthine phosphoribosyltransferase activity measured using 6-mercaptopurine as a substrate: a population study in children with acute lymphoblastic leukaemia.

1. 6-Mercaptopurine (6-MP) is used in the continuing chemotherapy of childhood acute lymphoblastic leukaemia. The formation of red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) active metabolites, not the dose of 6-MP, is related to cytotoxicity and prognosis. But there is an apparent sex difference in 6-MP metabolism. Boys require more 6-MP than girls to produce the same range of 6-TGN concentrations. Given the same dose, they experience fewer dose reductions because of cytotoxicity, and have a higher relapse rate. 2. The enzyme hypoxanthine phosphoribosyltransferase (HPRT) catalyses the initial activation step in the metabolism of 6-MP to 6-TGNs, a step that requires endogenous phosphoribosyl pyrophosphate (PRPP) as a cosubstrate. Both HPRT and the enzyme responsible for the formation of PRPP are X-linked. 3. RBC HPRT activity was measured in two populations, 86 control children and 63 children with acute lymphoblastic leukaemia. 6-MP was used as the substrate and the formation of the nucleotide product, 6-thioinosinic acid (TIA) was measured. RBC 6-TGN concentrations were measured in the leukaemic children at a standard dose of 6-MP. 4. There was a 1.3 to 1.7 fold range in HPRT activity when measured under optimal conditions. The leukaemic children had significantly higher HPRT activities than the controls (median difference 4.2 micromol TIA ml(-1) RBCs h(-1), 95% C.I. 3.7 to 4.7, P < 0.0001). In the leukaemic children HPRT activity (range 20.4 to 26.6 micromol TIA ml(-1) RBCs h(-1), median 23.6) was not related to the production of 6-TGNs (range 60 to 1,024 pmol 8 x 10(-8) RBCs, median 323). RBC HPRT was present at a high activity even in those children with low 6-TGN concentrations. 5. When HPRT is measured under optimal conditions it does not appear to be the metabolic step responsible for the observed sex difference in 6-MP metabolism. This may be because RBC HPRT activity is not representative of other tissues but it could equally be because other sex-linked factors are influencing substrate availability.

Importance of 6-mercaptopurine dose in lymphoblastic leukaemia.

To explore the possibility that higher total dosage of 'maintenance' treatment may have contributed to the recent improvement in outlook of children in the United Kingdom with lymphoblastic leukaemia, details of the amount of 6-mercaptopurine prescribed during the first two years of treatment were studied in an unselected cohort of children diagnosed between 1973 and 1987. Eighty five patients were studied, 30 diagnosed before and 55 after 1980. The group diagnosed after 1980 showed an 18% improvement in relapse free survival at five years. Their median total dose of 6-mercaptopurine had increased by 22%, whereas according to the protocol it should have risen by an average of only 9%. After 1980 boys were prescribed significantly more 6-mercaptopurine than girls, and had fewer dose reductions because of myelosuppression. These findings support the clinical impression that after 1980 an important therapeutic difference resulting from the new United Kingdom acute lymphoblastic leukaemia protocols was an increase in the amount of 6-mercaptopurine that children actually received as a result of changes in prescribing guidelines rather than dose. They also provide further evidence that boys tolerate 6-mercaptopurine better than girls, which may be related to the still unexplained difference in prognosis between the sexes.

The morphology and ultrastructure of common inhibitory motor neurones in the thorax of the locust.

The morphologies of three common inhibitory motor neurones which innervate muscles of a hind leg and the homologous three neurones which innervate muscles in a middle leg are described in relation to known commissures, tracts, and areas of neuropile in their ganglia. The neurones were stained individually by the intracellular injection of cobalt, and the ultrastructure of common inhibitor 1 (CI1) in the metathoracic ganglion was revealed by the intracellular injection of horseradish peroxidase. Homologous inhibitory motor neurones in the meso- and metathoracic ganglia have similar shapes. CI1 has axons in nerves 3, 4, and 5, but common inhibitors 2 and 3 (CI2, CI3) have only a single axon in nerve 5. They nevertheless all share many features in common. All have large (60 70 micron diameter) cell bodies in the ventral cortex near the midline, well separated from those of the excitatory leg motor neurones. Their primary neurites run dorsally and laterally and send many fine branches into the dorsal and lateral neuropile, and some fine branches medially. None enter the ventral neuropile. CI1 and CI2 have a small branch that arises close to the cell body and arborises on either side of the midline. When examined with the electron microscope, CI1 was not found to make any output synapses, even though some of its fine branches are varicose and end in bulbous swellings. These were seen to be packed with mitochondria but not vesicles. Input synapses tend to be grouped together on the secondary neurites and, more especially, on the finer branches and their spines. The majority of processes presynaptic to CI1 contain round agranular vesicles.

Innervation patterns of inhibitory motor neurones in the thorax of the locust.

The innervation pattern of inhibitory motor neurones of the locust has been revealed by intracellular recording from their cell bodies in the meso- and metathoracic ganglion and simultaneous recording from muscle fibres in a middle, or in a hind leg. Three neurones in each ganglion, the common inhibitor (CI = CI1), the anterior inhibitor (AI = CI2), and the posterior inhibitor (PI = CI3) innervate several muscles in one leg and are thus common inhibitory neurones. Metathoracic CI innervates 13 muscles in one hind leg and mesothoracic CI innervates 12 muscles in one middle leg. The muscles are all in the proximal parts of the legs and move the coxa, the trochanter and the tibia. Metathoracic AI and PI innervate four muscles in the more distal parts of one hind leg that move the tibia, the tarsus and the unguis. None of these muscles is innervated by CI. Each inhibitor innervates muscles that have different and often antagonistic actions during movements of a leg. AI and PI receive many synaptic inputs in common and show similar patterns of spikes during imposed movements of a tibia. Tests fail, however, to reveal evidence for any electrical or synaptic coupling between them. A revised scheme of nomenclature for these inhibitory neurones is proposed.