In-phantom characterisation studies at the Birmingham Accelerator-Generated epIthermal Neutron Source (BAGINS) BNCT facility.

A broad experimental campaign to validate the final epithermal neutron beam design for the BNCT facility constructed at the University of Birmingham concluded in November 2003. The final moderator and facility designs are overviewed briefly, followed by a summary of the dosimetric methods and presentation of a small subset of the results from this campaign. The dual ionisation chamber technique was used together with foil activation to quantify the fast neutron, photon, and thermal neutron beam dose components in a large rectangular phantom exposed to the beam with a 12 cm diameter beam delimiter in place. After application of a normalisation factor, dose measurements agree with in-phantom MCNP4C predictions within 10% for the photon dose, within 10% for thermal neutron dose, and within 25% for the proton recoil dose along the main beam axis.     

Management of Finnish congenital nephrotic syndrome by unilateral nephrectomy

Finnish congenital nephrotic syndrome is fatal unless managed aggressively; treatment in hospital with albumin infusions and subsequent bilateral nephrectomy allows survival. However, it consistently results in protein malnutrition which may lead to serious infections and severe physical and developmental retardation, as well as the subsequent burden of dialysing an anephric child. We treated a boy by unilateral nephrectomy at 3 months. The reduced protein loss allowed home management with albumin infusions and resulted in a substantial rise in his plasma IgG levels. The glomerular filtration rate declined fairly rapidly after unilateral nephrectomy, so he needed peritoneal dialysis by 16 months, which was straightforward as he still maintained a good urine output. Management by unilateral nephrectomy has allowed this boy to grow and develop normally. The time spent in hospital was minimal and the very high cost of providing albumin preparations was reduced considerably.     

Stress as a diagnostic challenge for psychiatric disorders

At the Stress Clinic we are investigating nine areas in which stress factors may play an important part: social habits, social relationships, life events, psychiatric, sexual, sleep, geriatric, menstrual and stress and the heart. The degree of stress in each area is quantified and a stress profile constructed for each patient. Thus, the relationships between the different stresses can be assessed and appropriate treatment advised. Inter-rater reliability in assessing the different items comprising the stress profile has shown a high degree of correlation for all items (P<O.Ol). On analysis of the records of the first 45 patients, the commonest principal diagnosis was depression (47 per cent), followed by anxiety (27 per cent), whilst in 17 per cent the main stress was insomnia and in three patients an organic illness (7 per cent) was the cause of the stress problems. The stress profile is also used to assess improvement and analysis of the first 18 cases demonstrated a significant reduction in many stress areas which was coincident with response to treatment.     

Increases in adipose and total body weight,but not in lean body mass,associated with subcutaneous administration of Sonic hedgehog‐Ig fusion protein to mice

Sonic hedgehog (Shh) is a member of a family of proteins that are involved in embryonic development. The receptor signaling pathways for Shh persist in adults and stimulation of this pathway has shown therapeutic efficacy in animal models of neurodegeneration/regeneration. This study was conducted to evaluate the safety of repeat dose administration of an IgG fusion protein of Shh (Shh‐Ig) in adult mice. Routine toxicology evaluations were performed. In addition, body composition analysis was conducted by densitometry. Shh‐Ig treatment caused a significant increase in body weight gain relative to controls and a slight increase in liver and spleen weights. The increase in body weight could be largely accounted for by an increase in body fat. The treatment‐related increases in body weight were reversible upon cessation of treatment. Shh‐Ig treatment produced no significant changes in clinical chemistry or hematology. There were no gross or histomorphologic findings in any tissue except for skin and spleen. Microscopic findings in the skin were limited to minimal to slight local epidermal hyperplasia at the sc injection site and increased thickness of the fat layer. In the spleen a slight increase in extramedullary hematopoiesis was seen. This finding is possibly a secondary response following inflammation at the injection site in some animals due to the administration of a foreign protein. This study showed that Shh‐Ig administration was well tolerated. The most significant finding was a reversible increase in body weight. Drug Dev. Res. 57:107–114, 2002. © 2002 Wiley‐Liss, Inc.     

7th Jan Waldenstr?m Lecture. The biology of human cancer metastasis.

The process of cancer metastasis is dynamic and consists of sequential, interrelated steps. Malignant cells that produce metastases have survived a series of potentially lethal interactions that are regulated by both the intrinsic properties of the tumor cells and host factors. Although some of the steps in this process contain stochastic elements, metastases develop from the nonrandom survival of a few subpopulations of cells that preexist within the parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of different cells. The orthotopic implantation of human cancer cells derived from surgical specimens into nude mice provides a biological model of metastasis. Using this model, clonal analysis of a human renal carcinoma, colon carcinoma, and melanoma has revealed that these tumors are heterogeneous for metastatic properties. Damage to an organ's environment is followed by inflammation and repair, and these homeostatic processes facilitate the proliferation of normal (physiology), and in some cases, tumor cells (pathology). Accelerated growth of human colon cancer cells was found in hepatectomized nude mice, whereas accelerated growth of human renal cancer cells was found in nephrectomized nude mice. These data suggest that systemic physiological signals can be usurped by neoplastic cells. Collectively, the factors that regulate metastasis are the intrinsic properties of metastatic cells and host factors involved in homeostasis.     

Immunohistochemically demonstrated altered expression of cytochrome P-450 molecular forms and epoxide hydrolase in N-ethyl-N-hydroxyethylnitrosamine-induced rat kidney and liver lesions

A comparison of N-ethyl-N-hydroxyethylnistrosamine (EHEN)-inducedpreneoplastic and neoplastic lesions in the rat liver and kidneywas made with respect to the expression of different drug metabolizingenzymes. Four cytochrome P-450 species (cyt. P-450 UT₅₀, PB_3a,MC₁ and MC₂) and microsomal epoxide hydrolase (mEHb) were investigatedalong with two glutathione S-transferase species (GST-P andA forms) earlier shown to be elevated in putative preneoplasticlesions in the liver and kidney, respectively. In contrast tothe liver lesions, which showed clear decrease in all formsof cyt. P-450s and increase of mEHb, elevated levels of cyt.P-450 PB_3a and, to a lesser extent, the other P-450 forms andearly elevation to late decrease in mEHb characterized the renaltubular lesions. Thus opposite shift in enzyme phenotype wasobserved in carcinogen-induced focal lesions of the two organs.Variation in binding levels in the different nephron segmentsand zones of the liver acinus indicated physiological specializationwith regard to the enzymes investigated and suggested that thealtered phenotype of preneoplastic populations might be of adaptivesignificance.     

A case-control interview study of breast cancer among Japanese A-bomb survivors. II. Interactions with radiation dose

Three breast cancer risk factors were evaluated in terms of their interactions with radiation dose in a case-control interview study of Japanese A-bomb survivors. Cases and controls were matched on age at the time of the hombings and radiation dose, and dose-related risk was estimated from cohort rather than case-control data. Each factor—age at first full-term pregnancy, number of deliveries, and cumulative lactation period summed over births—conformed reasonably well to a multiplicative interaction model with radiation dose (the additive interactive model, in which the absolute excess risk associated with a factor is assumed to be independent of radiation dose, was rejected). An important implication of the finding is that early age at first full-term pregnancy, multiple births, and lengthy cumulative lactation are all protective against radiation-related, as well as baseline, breast cancer. Analyses by age at exposure to radiation suggest that, among women exposed to radiation in childhood or adolescence, a first full-term pregnancy at an early agefollowing exposure may be protective against radiation-related risk.The Radiation Effects Research Foundation (formerly the Atomic Bomb Casualty Commission) was established in April 1975 as a private nonprofit Japanese Foundation, supported equally by the Government of Japan through the Ministry of Health and Welfare, and the Government of the United States through the National Academy of Sciences under contract with the Department of Energy. The present work was performed as part of a collaboration between RERF and the US National Cancer Institute.