European collaboration in trials of new agents for children with cancer.

Childhood cancer is a relatively rare disease, representing just 1% of all malignancies. Within Europe, this represents some 12,000 new cases each year, with approximately 1600 a year in the United Kingdom and 1800 in France. International collaboration in phase III trials of childhood cancer has been the norm for many years, traditionally within Europe, but, largely because of organisational considerations, phase I and II trials have only been conducted on a national basis. With overall cure rates in the region of 70%, relatively few children are available for these early drug trials. Access to new drugs is also a major problem. Against this background, a United Kingdom (UK)/French 'new agent' collaboration was established, expanding subsequently into a wider European grouping. This paper documents the history of that collaboration, the outcomes and future challenges.

Ethical approval for multicentre clinical trials in children. Contrasting systems in three European countries.

Pan-European collaboration in studies of novel therapies and treatment strategies in childhood cancer is playing an increasing role in the attempt to improve cure rates. Differences in the systems of various countries with regard to drug control and ethical issues may lead to problems and delays. This applies in particular to phase I/II studies in children where the ethical considerations may be complex. In this review, the systems in three large countries-UK, France and Germany-are reviewed and current moves within the European Community towards a more standard approach are discussed.

Application of the NMR-MOUSE to food emulsions.

The application of the NMR-MObile Universal Surface Explorer (NMR-MOUSE) to study food systems is evaluated using oil-in-water emulsions, and the results are compared to those obtained using a conventional low-field NMR (LF-NMR) instrument. The NMR-MOUSE is a small and portable LF-NMR system with a one-sided magnet layout that is used to replace the conventional magnet and probe on a LF-NMR instrument. The high magnetic field gradients associated with the one-sided MOUSE magnet result in NMR signal decays being dominated by molecular diffusion effects, which makes it possible to discriminate between the NMR signals from oil and water. Different data acquisition parameters as well as different approaches to the analysis of the NMR data from a range of oil-in-water emulsions are evaluated, and it is demonstrated how the concentration of oil and water can be determined from the NMR-MOUSE signals. From these model systems it is concluded that the NMR-MOUSE has good potential for the quantitative analysis of intact food products.

A test material for tissue characterisation and system calibration in MRI.

A tissue-equivalent test material for MRI has been produced from a polysaccharide gel, agarose, containing gadolinium chloride chelated to EDTA. By varying the amounts of each constituent, the T1 and T2 of the material can be varied independently. As a result, the entire range of in vivo tissue relaxation times can be covered. Through the mathematical modelling of the 1H relaxation theories for both the gel and chelated paramagnetic ion, it has been possible to create a material with relaxation properties and behaviour predictable as functions of both the Larmor frequency and temperature. The similarity of the material to in vivo tissues, in terms of its biological and physical NMR characteristics, makes it an excellent tissue-equivalent substance, in addition to being an accurate calibration standard for routine MRI.

Short echo time MRI enables visualisation of the natural state of human stratum corneum water in vivo.

High resolution magnetic resonance imaging studies on skin have been limited by their inability to detect the low-moisture-content outer layers near the surface of the stratum corneum. The hydration of these outer layers is especially important physiologically. The present study shows that by using a short echo time of 5 ms it becomes possible to observe these layers in all but a few individuals with exceptionally dry skin. The quality of the images can be further improved by the use of separate transmit and receive coils, which reduces the rapid fall-off in signal intensity encountered with a single surface coil used both to transmit and receive.

Rapid MRI and velocimetry of cylindrical Couette flow.

A narrow-gap, temperature-controlled Couette flow rheometer has been developed to study fluid velocities within the annular gap between two concentric cylinders by nuclear magnetic resonance (NMR) imaging and velocimetry. Alternative pulsed-field-gradient-based nuclear magnetic resonance imaging strategies which may be used for measurement of velocity within the Couette flow device have been evaluated. These include two-dimensional (2-D) imaging techniques with acquisition times of several minutes and a one-dimensional (1-D) projection method which exploits the symmetry of the device to reduce overall measurement time to less than 1 min. Velocity measurements made using each technique are presented for a Newtonian fluid undergoing Couette flow at shear rates of approximately 20 and 60 s(-1).

The effect of mechanical deformation on the movement of water in foods.

This study has shown the importance of relating NMR spectroscopic information on the water in model food structures to the mechanical properties of those structures. Analysis of the NMR relaxation data can be used to examine the distribution of water domain sizes, and this has been related to the mechanical properties of the samples. A novel NMR probe-head has been designed, which allows both the NMR and the mechanical data to be simultaneously measured during compression of the sample. This probe-head allows compressive stress/strain data to be obtained directly from the NMR sample, allowing changes in the distribution of the water to be directly correlated to changes in mechanical properties.

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours.

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

Recruiting children into cancer trials--role of the United Kingdom Children's Cancer Study Group (UKCCSG).

The UK Children's Cancer Study Group (UKCCSG), established in 1977, provides a highly organised structure for both service provision and research, and represents the model to which the adult cancer community is currently aspiring. Since childhood cancer is so rare, it is both essential and feasible for the vast majority of children to be referred into the network of specialist centres, and also for the maximum number of children to be recruited into national and international clinical trials. Over the last 30-40 years there have been major advances in treatment, such that now approximately 70% of children diagnosed with cancer will be cured of their disease. The conduct of clinical trials in this patient population does, however, raise a number of specific issues and these are discussed in the paper.

Moisturization processes in living human skin studied by magnetic resonance imaging microscopy.

Summary Magnetic resonance imaging is a non-invasive, non-destructive and chemically specific imaging method widely used in medicine to reveal information about both tissue structure and function. It can measure water in tissue, but it has been difficult to achieve the necessary sensitivity and resolution when applying it to studies of the dry, thin stratum corneum. In this paper the use of magnetic resonance imaging to image the outer layers of the skin with a resolution of 0.06 mm is reported. Configuring the magnetic resonance imaging method in this way has made it possible for the first time to actually 'see'directly the moisturization in the stratum corneum. It is no longer necessary to rely upon methods which can only show side-effects of moisturization, such as changes in the appearance of the skin cells. As magnetic resonance imaging is harmless, it can be used repeatedly on the same skin and so produce a series of stills, or a time-lapse video, clearly showing the actual process of moisturization and related phenomena. The behaviour of skin has been observed during both hydration and dehydration; the two processes follow different time courses. Two layers have been observed in the stratum corneum, which appear to be different when the skin is hydrated. For the first time the actual surface of normal skin has been revealed on magnetic resonance images.

Phase I trials in paediatric oncology--the European perspective. The New Agents Group of the United Kingdom Childrens Cancer Study Group.

The current recommendations for Phase I trials should allow more confident interpretation of the toxicity and efficacy of new agents by providing a framework for multicentre and international co-operation. An overview of the aims and designs of Phase I trials is presented, along with a summary of current and recently published United Kingdom Childrens Cancer Study Group Phase I trials, and a discussion of some of the difficulties faced in the methodology and evaluation of Phase I studies in children.

Strategies for Rapid NMR Rheometry by Magnetic Resonance Imaging Velocimetry

Strategies for NMR-based rheometry are discussed with particular attention given to ease of implementation, robustness, and measurement speed. The techniques are based on NMR velocimetry of Poiseuille flow, and together with measurements of the pressure drop, the velocimetric data may be processed to yield measures of the shear viscosity over the range of shear rates present in the Poiseuille flow field of the test fluid. Methods for NMR velocimetry are briefly reviewed, and three methods all based on the pulsed-field-gradient technique are compared experimentally; they involve (1) direct two-dimensional imaging of the tube cross section, (2) one-dimensional imaging of a Cartesian projection of the tube cross section followed by Abel inversion to obtain radial profiles, and (3) measurement of the bulk velocity spectrum of the tube cross section and conversion to the radial velocity profile. The second and third of these techniques allow the most rapid measurements (potentially less than one minute) and show promise for on-line NMR rheometry.

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.