Quantitative Delta T1 (dT1) as a Replacement for Adjudicated Central Reader Analysis of Contrast-Enhancing Tumor Burden: A Subanalysis of the American College of Radiology Imaging Network 6677/Radiation Therapy Oncology Group 0625 Multicenter Brain Tumor Trial.

BACKGROUND AND PURPOSE: Brain tumor clinical trials requiring solid tumor assessment typically rely on the 2D manual delineation of enhancing tumors by ≥2 expert readers, a time-consuming step with poor interreader agreement. As a solution, we developed quantitative dT1 maps for the delineation of enhancing lesions. This retrospective analysis compares dT1 with 2D manual delineation of enhancing tumors acquired at 2 time points during the post therapeutic surveillance period of the American College of Radiology Imaging Network 6677/Radiation Therapy Oncology Group 0625 (ACRIN 6677/RTOG 0625) clinical trial. MATERIALS AND METHODS: Patients enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized Phase II trial of bevacizumab in recurrent glioblastoma, underwent standard MR imaging before and after treatment initiation. For 123 patients from 23 institutions, both 2D manual delineation of enhancing tumors and dT1 datasets were evaluable at weeks 8 (n = 74) and 16 (n = 57). Using dT1, we assessed the radiologic response and progression at each time point. Percentage agreement with adjudicated 2D manual delineation of enhancing tumor reads and association between progression status and overall survival were determined. RESULTS: For identification of progression, dT1 and adjudicated 2D manual delineation of enhancing tumor reads were in perfect agreement at week 8, with 73.7% agreement at week 16. Both methods showed significant differences in overall survival at each time point. When nonprogressors were further divided into responders versus nonresponders/nonprogressors, the agreement decreased to 70.3% and 52.6%, yet dT1 showed a significant difference in overall survival at week 8 (P = .01), suggesting that dT1 may provide greater sensitivity for stratifying subpopulations. CONCLUSIONS: This study shows that dT1 can predict early progression comparable with the standard method but offers the potential for substantial time and cost savings for clinical trials.

Regional distribution of iron, transferrin, ferritin, and oxidatively-modified proteins in young and aged Fischer 344 rat brains.

Iron dysregulation in the brain is thought to contribute to the oxidative damage seen in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. A role for iron in the oxidative stress thought to contribute to normal ageing is less certain. To better characterize the role of iron in normal ageing, the concentrations of iron, transferrin, ferritin, and protein carbonyl groups are measured in nine separate regions of Fischer 344 rats. The largest (approximately 30%) age-related increases in brain iron concentration are seen in the temporal cortex, medial septum, and cerebellum. Ferritin concentration in these same brain regions increases 50 to 250% with age, while protein carbonyl concentration is only -27 to +4%, of young rats. These results indicate that an increase in the major iron-binding protein ferritin compensates for any age-related increase in iron concentration, and suggest that the increased ferritin is cytoprotective, serving to prevent the accumulation of protein carbonyl groups (a principal product of metal-catalysed oxidation of proteins).

Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions.

Oxidant-mediated damage is suspected to be involved in the pathogenesis of several neurodegenerative disorders. Iron promotes conversion of hydrogen peroxide to hydroxyl radical and, thus, may contribute to oxidant stress. We measured iron and its transport protein transferrin in caudate, putamen, globus pallidus, substantia nigra, and frontal cortex of subjects with Alzheimer's disease (n = 14) and Parkinson's disease (n = 14), and in younger adult (n = 8) and elderly (n = 8) normal controls. Although there were no differences between control groups with regard to concentrations of iron and transferrin, iron was significantly increased (p < 0.05) in Alzheimer's disease globus pallidus and frontal cortex and Parkinson's disease globus pallidus, and transferrin was significantly increased in Alzheimer's disease frontal cortex, compared with elderly controls. The transferrin/iron ratio, a measure of iron mobilization capacity, was decreased in globus pallidus and caudate in both disorders. Regional transferrin and iron concentrations were generally more highly correlated (Pearson's correlation coefficient) in elderly controls than in Alzheimer's and Parkinson's disease. The altered relationship between iron and transferrin provides further evidence that a disturbance in iron metabolism may be involved in both disorders.

A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains.

The brain requires a ready supply of iron for normal neurological function, but free iron is toxic. Consequently, iron bioavailability must be stringently regulated. Recent evidence has suggested that the brain iron regulatory system is dysfunctional in neurological disorders such as Alzheimer's and Parkinson's diseases (AD and PD, respectively). A key component of the iron regulatory system in the brain is ferritin. Ferritin consists of 24 subunits, which are distinguished as either a heavy-chain (H) or light-chain (L) isoform. These peptide subunits are genetically and functionally distinct. Thus, the ability to investigate separately the types of ferritin in brain should provide insight into iron management at both the cellular and the molecular level. In this study, the ratio of isoferritins was determined in select regions of adult elderly AD and PD human brains. The H-rich ferritin was more abundant in the young brain, except in the globus pallidus where the ratio of H/L ferritin was 1:1. The balance of H/L isoferritins was influenced by age, brain region, and disease state. With normal aging, both H and L ferritin increased; however, the age-associated increase in isoferritins generally failed to occur in AD and PD brain tissue. The imbalance in H/L isoferritins was disease and region specific. For example, in frontal cortex, there was a dramatic (fivefold) increase in the ratio of H/L ferritin in AD brains but not in PD brains. In PD, caudate and putamen H/L ratios were higher than in AD and the elderly control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer's disease.

It is well established that iron, which is of considerable importance for normal neurological function, is highly regulated in all organ systems. However, until recently, iron regulation in the nervous system has received little attention. This study quantitatively compares the levels of the major iron-regulatory proteins, transferrin and ferritin, and iron itself in three cerebral cortical regions of the human brain from material collected at autopsy. Three groups were studied: 1) normal adult (under 65 yr of age), 2) aged (greater than 65), and 3) Alzheimer's disease. Normally, transferrin is more abundant in white matter than in gray matter. Ferritin is approximately 10x more abundant than transferrin throughout the brain regions examined and is evenly distributed, as is iron, in the gray and white matter. In Alzheimer's disease transferrin is consistently decreased particularly in the white matter of the various cerebral cortical regions examined whereas the iron and ferritin changes are inconsistent. The observations in this study are consistent with our general hypothesis that iron homeostasis is disrupted in the aging brain and the alterations in iron-regulatory proteins are exacerbated in Alzheimer's disease. The decrease in transferrin levels could indicate a decreased mobility and subsequent utilization of iron in the brain. Such a decrease in iron availability could play a significant role in neuronal degeneration and increased peroxidative damage known to occur in Alzheimer's disease.

Antiferromagnetism in Pressure-Amorphized Fe2SiO4.

Amorphous Fe(2)SiO(4) synthesized at elevated pressures exhibits a Néel transition at a temperature identical to that observed in the crystalline form, T(N) = 65 (+/-2) kelvin at zero pressure. This behavior contrasts sharply with observations on other disordered systems, such as spin glasses, which characteristically exhibit strong "frustration" of the spins and consequent marked suppression of the Néel transition.

Transferrin expression in myelinated and non-myelinated peripheral nerves.

Transferrin and its receptor are involved in the delivery of iron to most cells. Previous studies have demonstrated that transferrin is associated with oligodendrocytes, the myelin-producing cells in the central nervous system. In the peripheral nervous system, the Schwann cell produces myelin. This study used immunohistochemistry and immunoblot analysis to determine whether expression of transferrin is unique to myelinated peripheral nerves. Immunohistochemical examination demonstrated cytoplasmic accumulation of transferrin in Schwann cells of the myelinated sciatic nerve, but not in the unmyelinated cervical sympathetic trunk. Immunoblot analysis revealed there is 10 X the amount of transferrin in the sciatic nerve compared to the cervical sympathetic trunk. These results are consistent with the hypothesis that transferrin may play a role in myelination.

Rees-Stealy merges with the future.

Last year's merger of the 60-year-old Sharp Rees-Stealy Medical Group and the San Diego Hospital Association was watched closely by groups around the Country who are considering similar arrangements. A look one year later shows that the merger has met the group's expectations.