Research priorities for children's cancer: a James Lind Alliance Priority Setting Partnership in the UK.

OBJECTIVES: To engage children who have experienced cancer, childhood cancer survivors, their families and professionals to systematically identify and prioritise research questions about childhood cancer to inform the future research agenda. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative. Potential research questions were collected in an online survey, then checked to ensure they were unanswered. Shortlisting via a second online survey identified the highest priority questions. A parallel process with children was undertaken. A final consensus workshop was held to determine the Top 10 priorities. PARTICIPANTS: Children and survivors of childhood cancer, diagnosed before age 16, their families, friends and professionals who work with this population. RESULTS: Four hundred and eighty-eight people submitted 1299 potential questions. These were refined into 108 unique questions; 4 were already answered and 3 were under active study, therefore, removed. Three hundred and twenty-seven respondents completed the shortlisting survey. Seventy-one children submitted questions in the children's surveys, eight children attended a workshop to prioritise these questions. The Top 5 questions from children were taken to the final workshop where 23 questions in total were discussed by 25 participants (young adults, carers and professionals). The top priority was 'can we find effective and kinder (less burdensome, more tolerable, with fewer short and long-term effects) treatments for children with cancer, including relapsed cancer?' CONCLUSIONS: We have identified research priorities for children's cancer from the perspectives of children, survivors, their families and the professionals who care for them. Questions reflect the breadth of the cancer experience, including diagnosis, relapse, hospital experience, support during/after treatment and the long-term impact of cancer. These should inform funding of future research as they are the questions that matter most to the people who could benefit from research.

Statins do not alter the incidence of mesothelioma in asbestos exposed mice or humans.

Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44-2.29, p = 0.99). Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61-1.67, p = 0.97). We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos.

The use of an integrated electroanatomic mapping system and intracardiac echocardiography to reduce radiation exposure in children and young adults undergoing ablation of supraventricular tachycardia.

AIMS: Non-fluoroscopic imaging (NFI) devices are increasingly used in ablations. The objective was to determine the utility of intracardiac echocardiography (ICE) in ablating paediatric supraventricular tachycardias (SVTs) and assess whether its integrated use with electroanatomic mapping (EAM) resulted in lower radiation exposure than use of EAM alone. METHODS AND RESULTS: Prospective, controlled, single-centre study of patients (pts) age ≥10 years, weight ≥35 kg, with SVT and normal cardiac anatomy. Patients were randomized to ICE + EAM (ICE) or EAM only (no ICE). Both had access to fluoroscopy as needed. Eighty-four pts were enroled (42 ICE, 42 no ICE). Median age was 15 years (range 10.4-23.7 years); 57% had accessory pathways, 42% atrioventricular nodal reentry tachycardia. There was no difference in radiation dose (9 mGy ICE vs. 23 mGy no ICE, P = 0.37) or fluoroscopy time (1.1 min ICE vs. 1.5 min no ICE, P = 0.38). Transseptal punctures were performed in 25 pts (16 ICE, 9 no ICE), with ICE reducing radiation (8 mGy ICE vs. 62 mGy no ICE, P = 0.002) and fluoroscopy time (1.1 min ICE vs. 4.5 min no ICE, P = 0.01). Zero fluoroscopy was achieved in 13 pts (15% of total, 5 ICE, 8 no ICE), and low-dose cases (<50 mGy) in 57 pts (68% of total, 33 ICE, 24 no ICE). Acute success was 95% for ICE, 88% for no ICE. CONCLUSION: Use of an integrated EAM/ICE system was no better than EAM alone in limiting radiation, but can be helpful for transseptal punctures. Given the low dose savings, use of ICE may be weighed against its financial cost. Low-fluoroscopy cases are performed in most NFI procedures.

The antioxidants vitamins A and E and selenium do not reduce the incidence of asbestos-induced disease in a mouse model of mesothelioma.

Epidemiological evidence indicates that supplementation with some dietary factors is associated with a lower incidence of cancer. An effective cancer prevention strategy for the millions of people worldwide who have been exposed to asbestos could have enormous benefit. We tested whether dietary supplementation of the antioxidants vitamin A, E, and selenium could alter the pattern of disease in the MexTAg transgenic mouse model, in which mice uniformly develop mesothelioma after asbestos exposure. We focused on antioxidants because one of the most widely accepted hypotheses for the mechanism by which asbestos fibers cause cancer proposes the involvement of reactive oxygen and nitrogen species. We compared the survival of MexTAg mice that had been inoculated with asbestos fed on diets supplemented with 250,000 IU/kg vitamin A (retinoic acid), or 1,000 mg/kg vitamin E (α-tocopherol acetate) or 3 mg/kg selenium, or both vitamin E and selenium concurrently and, additionally, diets deficient in each antioxidant. We found that neither the time to develop symptoms of disease nor overall survival times were altered by any of the diets. We conclude that the data do not support the notion that dietary antioxidants will moderate the rate of mesothelioma in asbestos-exposed populations.

Nutritional sensitivity of fifth instar prothoracic glands in the tobacco hornworm, Manduca sexta.

Insulin-regulated growth of the prothoracic glands appears to play a critical role in timing the last larval molt, and hence metamorphosis. The present study examined insulin signaling in relation to the growth and secretory activity of prothoracic glands in the tobacco hornworm, Manduca sexta. As larvae feed during the first half of the final larval stage, the prothoracic glands grow and ecdysone secretory capacity increases. During this period of growth, we verified the presence of insulin receptor transcript in the prothoracic glands and demonstrated that the glands were responsive to insulin, as evidenced by the in vitro phosphorylation of signaling proteins in the insulin pathway such as Akt/protein kinase B and FOXO. It was predicted that starvation would reduce ecdysone secretion with concomitant changes in insulin signaling. To test this prediction, larvae were starved and changes were quantified in two nutritionally sensitive transcripts, insulin receptor and the translation inhibitor 4EBP. In glands from starved larvae, growth and ecdysone secretory capacity were reduced, and insulin receptor and 4EBP transcripts were increased. The latter changes would be expected to accompany starvation in conjunction with enhanced insulin sensitivity and reduced protein synthesis. Increased transcription of insulin receptor and 4EBP strongly suggest that nutritional deprivation reduces the secretion of endogenous insulin-like hormones. When injected with insulin, 4EBP levels in the prothoracic glands of starved larvae decreased. Thus, insulin appeared to correct starvation-induced deficits in glandular protein synthesis. However, insulin injection did not enhance ecdysone secretion. Thus, although the prothoracic glands are insulin-responsive and insulin-like hormones may promote glandular growth as larvae feed, the effects of nutritional depletion on steroidogenesis in Manduca cannot be explained solely by reduced insulin.

MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma.

Animal models provide an important tool for investigating the biology of cancer and for testing the efficacy of novel treatments. Here we describe several aspects of the transgenic MexTAg mouse that develops asbestos-induced mesothelioma. Targeted expression of the TAg transgene causes mesothelioma to develop more rapidly after asbestos exposure in wild-type mice with 100% incidence compared to 30% incidence in wild-type mice. MexTAg mice do not develop spontaneous mesothelioma and exhibit a very low incidence of other tumours. Here we show that TAg does not affect the aggressiveness or rate of progression of the mesotheliomas, suggesting that the oncogene alters only the rate at which disease is initiated. The instillation of an alternative inflammatory agent, thioglycollate, did not induce mesotheliomas, demonstrating acute inflammation is not sufficient for tumour development in MexTAg mice. We found that neither the age of a mouse at the time of exposure nor its gender were prognostic factors. MexTAg mice with mesotheliomas respond to treatment with a cytotoxic drug in a similar way to that of patients with mesothelioma, demonstrating the validity of the model. We also show that long-term treatment with a COX-2 inhibitor prior to the development of disease does not have a survival benefit, suggesting that this is not a useful cancer prevention therapy for asbestos-exposed individuals. The model is robust and suitable for testing a wide variety of protocols and a range of translational studies.

Endoscopic decompression of intermetatarsal nerve entrapment: a retrospective study.

Sixty-nine patients who had 96 interspaces decompressed were retrospectively reviewed to assess the efficacy of the endoscopic decompression of the intermetatarsal nerve procedure. Cases were evaluated between October 1, 1993, and December 31, 1999. Of the 69 patients, 14 were men and 55 were women, and their average age was 50.6 years. Of the 96 interspaces released, 39 were second interspaces and 57 were third interspaces. Nine interspaces were lost to follow-up. There were 75 interspaces with excellent or good results (86%) and 12 with poor results (14%). Of the interspaces with poor results, five required further surgery. Those five interspaces, in five patients, were treated with traditional neurectomy. The other patients, accounting for seven interspaces, who classified their result as poor declined any further surgery. Evaluation of these cases was by means of medical chart review only, where the patient's success or failure was based on the patient's subjective assessment. None of the patients who underwent decompression developed a true amputation neuroma.

Relationship between red blood cell thiopurine methyltransferase activity and myelotoxicity in dogs receiving azathioprine.

Thiopurine methyltransferase (TPMT) produces inactive metabolites of azathioprine and, in humans, has a variable amount of activity. Humans with low TPMT activity commonly develop myelotoxicity when receiving azathioprine. Our study sought to characterize the distribution of TPMT activity in a population of dogs and to determine whether the pretreatment knowledge of red blood cell (RBC) TPMT activity could predict myelotoxicity in dogs receiving azathioprine. RBC TPMT activity was measured in 299 healthy dogs, and 9 dogs that represented a wide range of enzyme activity received azathioprine at a standard therapeutic dose for 30 days. TPMT activity in healthy dogs was log normally distributed and varied over an approximately 7-fold range. Geometric mean, minimum, and maximum RBC TPMT activities were 37.1, 16.3, and 115 nmol per gram of hemoglobin (gHb) per hour, respectively. TPMT deficiency was not identified. Two populations of TPMT activity in dogs were detected by statistical modeling (commingling analysis). Dogs with intermediate TPMT activity (14-38 nmol/gHb/h) receiving azathioprine had significantly lower neutrophil counts during week 4 than during weeks 0-3, whereas those with high activity (>39 nmol/gHb/h) did not have a significant change in neutrophil count. An analysis of TPMT activity in 6 dogs with a history of azathioprine-associated myelotoxicity in a clinical setting revealed either intermediate or high TPMT enzyme activity in all dogs, suggesting that TPMT activity, as measured in RBCs, is not the sole cause of severe azathioprine-associated myelosuppression in dogs.